Haloalkylguanidine compounds, pharmaceutical compositions and methods, processes and intermediates

ABSTRACT

The invention relates to guanidine derivatives which are histamine H-2 antagonists and which inhibit gastric acid secretion. According to the invention there is provided a guanidine derivative of the formula I:- ##STR1## in which R 1  and R 2 , same or different, are hydrogen or 1-10C alkyl, 3-8C cycloalkyl or 4-14C cycloalkylalkyl, each alkyl, cycloalkyl or cycloalkylalkyl optionally carrying one or more F, Cl or Br atoms, provided that one of R 1  and R 2  is halogen substituted, or R 2  is hydrogen and R 1  is R 5  --E--W in which W is 2-6C alkylene optionally substituted by 1 or 2 1-4C alkyls, E is O,S or NR 6  in which R 6  is H or 1-6C alkyl, R 5  is H or 1-6C alkyl optionally substituted by 1 or 2 1-4C alkyls, or R 5  and R 6  are joined to form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring; ring X is a heterocyclic ring as defined in the specification; A is phenylene or 5-7C cycloalkylene, or a 1-8C alkylene into which is optionally inserted one or two groups; D is O or S; and R 3  and R 4  are hydrogen or a variety of radicals described in the specification: and the pharmaceutically-acceptable acid-addition salts thereof. Manufacturing processes and pharmaceutical compositions are also described.

This invention relates to guanidine derivatives which are histamine H-2antagonists and which inhibit gastric acid secretion.

It is postulated that the physiologically-active compound histamine,which occurs naturally within the animal body, is able to combine, inthe course of exerting its activity, with certain specific receptors ofwhich there are at least two distinct and separate types. The first hasbeen named the H-1 receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27,427) and the action of histamine at this receptor is blocked(antagonised) by classical "antihistamine" drugs such as mepyramine. Thesecond histamine receptor has been named the H-2 receptor (Black et al.,Nature, 1972, 236, 385) and the action of histamine at this receptor isblocked by drugs such as cimetidine. It is known that one of the resultsof the blockade of the action of histamine at the H-2 receptor is theinhibition of the secretion of gastric acid and a compound whichpossesses this ability is therefore useful in the treatment of pepticulcers and other conditions caused or exacerbated by gastric acidity.

In U.K. patent application No. GB2052478A and Japanese patentapplication No. J56108777 (Derwent Accession No. 74736 D/41) there aredescribed histamine H-2 receptor antagonists which are2-guanidinothiazole derivatives carrying a side chain in the 4-positionto the end of which is attached a carbamoyl group. It has now beendiscovered that a haloalkylguanidino-heterocycle carrying a side chainto the end of which is attached an optionally substituted carbamoylgroup is a potent histamine H-2 receptor antagonist.

According to the invention there is provided a guanidine derivative ofthe formula I: ##STR2## in which R¹ and R², which may be the same ordifferent, are hydrogen atoms or branched or unbranched 1-10C alkyl,3-8C cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl,cycloalkyl or cycloalkylalkyl radical being optionally substituted byone or more halogen atoms selected from fluorine, chlorine and bromineatoms, provided that at least one of R¹ and R² is a halogen-substitutedalkyl, halogen-substituted cycloalkyl or halogen-substitutedcycloalkylalkyl radical and provided there is no halogen-substituent onthe carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radicalwhich is directly attached to the nitrogen atom, or --R² is a hydrogenatom and --R¹ is a radical of the formula II:

    R.sup.5 --E--W--                                           II

in which W is an unbranched 2-6C alkylene chain which is optionallysubstituted by one or two 1-4C alkyl radicals, E is an oxygen or sulphuratom, a sulphinyl or sulphonyl radical, or a radical of the formula NR⁶in which R⁶ is a hydrogen atom or a 1-6C alkyl radical, R⁵ is a hydrogenatom or an unbranched 1-6C alkyl radical which is optionally substitutedby one or two 1-4C alkyl radicals, or R⁵ and R⁶ are joined to form,together with the nitrogen atom to which they are attached, apyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazinering; in ring X the dotted line is a double bond on one side of thenitrogen atom N and Z is a carbon or nitrogen atom such that ring X is a5- or 6-membered aromatic heterocyclic ring which contains at least onenitrogen atom and may optionally contain one or two additional heteroatoms selected from oxygen, nitrogen and sulphur atoms, whichheterocyclic ring may, where possible, carry one or two optionalsubstituents, the optional substituents on ring X being selected fromfluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy,trifluoromethyl, hydroxy and amino radicals;

A is a phenylene or 5-7C cycloalkylene radical or a 1-8C alkylene chainwhich is optionally substituted by one or two 1-3C alkyl radicals andinto which is optionally inserted, as part of the backbone of the chain,one or two groups selected from oxygen and sulphur atoms and NH, 1-6CN-alkyl, cis and trans vinylene, ethynylene, phenylene and 5-7Ccycloalkylene radicals, provided that the shortest link between ring Xand C═D is of at least 3 atoms, provided that when an optional insertionis made in chain A which results in the inserted group being directlyattached to C═D the inserted group is other than an oxygen or sulphuratom or an NH or N-alkyl radical, and provided that no two insertionsselected from oxygen and sulphur atoms and NH and N-alkyl radicals aredirectly attached one to the other;

D is an oxygen or sulphur atom, in particular an oxygen atom;

R³ is a hydrogen atom or a hydroxy, amino, 1-6C alkylamino, 1-6Chaloalkylamino, 1-6C alkanoylamino, 1-6C alkyl, 3-8C cycloalkyl, 4-12Ccycloalkylalkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C haloalkyl, (the haloor halos of the 1-6C haloalkylamino and the 1-6C haloalkyl beingselected from one or more of the group of fluorine, chlorine, bromineand iodine), 1-6C alkoxy, 1-6C hydroxyalkyl, 2-10C alkoxyalkyl, 2-10Calkylthioalkyl, 1-6C aminoalkyl, 2-8C alkylaminoalkyl, 3-12Cdialkylaminoalkyl, 2-8C alkanoylaminoalkyl, 8-14C aroylaminoalkyl, 3-10Calkoxycarbonylalkyl, 2-8C carbamoylalkyl, 6-10C aryl, 7-11C arylalkyl,heteroaryl or heteroarylalkyl radicals, wherein the heteroaryl part is aheterocyclic aromatic ring containing one, two or three hetero atomsselected from oxygen, nitrogen and sulphur atoms, wherein the alkyl partof the heteroarylalkyl radical is 1-6C and wherein, when R³ is orcontains an aryl or heteroaryl ring, that ring is optionally substitutedby one or two groups selected from fluorine, chlorine, bromine andiodine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, 2-6Cdialkylamino, 2-6C alkanoyl, trifluoromethyl, hydroxy and aminoradicals; R⁴ is a hydrogen atom or R³ is alkyl and R³ and R⁴ are joinedto form, together with the nitrogen atom to which they are attached, a5-, 6- or 7-membered saturated ring which optionally contains a doublebond or an additional oxygen atom, NH or 1-6C N-alkyl radical; and thepharmaceutically-acceptable acid-addition salts thereof.

It is to be understood that, in the above formula I and throughout thisspecification, although the double bond in the guanidine residueattached to ring X has been inserted in a particular position, othertautomeric forms are possible, and this invention includes suchtautomeric forms within its scope, both in terms of the compounds of theinvention and in terms of the manufacturing processes. It is also to beunderstood that when A is or contains a cycloalkylene radical the groupsattached to this radical may be in the cis or trans configuration. WhenA is or contains a cycloalkylene radical and/or when A is an alkylenechain substituted by one or two alkyl radicals the compound of theformula I will, in most instances, contain at least one asymmetriccentre. In such cases the compound of the formula I will therefore existin at least two enantiomeric forms, the precise number being determinedby the number of asymmetric centres. The biological activity, ashereinafter defined, of these enantiomeric forms may differ, and it istherefore to be understood that this invention encompasses the racemateof the formula I, including any possible diastereoisomeric forms, andany enantiomeric form which possesses the disclosed biological activity,it being a matter of common general knowledge to one skilled in the arthow to separate diastereoisomeric forms and how to separate a racemateinto its enantiomers and determine the biological activity of each.

A particular value for R¹ or R² when it is a halogen-substituted alkylradical is a 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2-bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl,2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl,2-chloro-2-fluoroethyl, 2-bromo-2-fluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl,1,1,1,3,3,3-hexafluoroisopropyl,1,3-dichloro-1,1,3,3-tetrafluoroisopropyl,1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl or2,2,3,3,4,4,4-heptafluorobutyl radical.

A particular value for R¹ or R² when it is a halogen-substitutedcycloalkyl radical is a 2,2,3,3-tetrafluorocyclopropyl,2-chloro-2,3,3-trifluorocyclopropyl, 2,2-difluorocyclopropyl,2-chloro-3,3-difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl or2-chloro-2,3,3,4,4-pentafluorocyclobutyl radical.

A particular value for R¹ or R² when it is a halogen-substitutedcycloalkylalkyl radical is a (1,2,2,3,3-pentafluorocyclopropyl)methyl,(2-chloro-1,2,3,3-tetrafluorocyclopropyl)methyl,(1,2,2,3,3,4,4-heptafluorocyclobutyl)methyl or(2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl)methyl radical.

A particular value for R¹ or R² when it is an alkyl radical is a methyl,ethyl, n-propyl, isopropyl or butyl radical.

A particular value for R¹ or R² when it is a cycloalkyl radical is acyclopropyl or cyclobutyl radical.

A particular value for R¹ or R² when it is a cycloalkylalkyl radical isa cyclopropylmethyl or cyclobutylmethyl radical.

A particular value for the optional substituent on W is a methylradical.

A particular value for R⁵ is a hydrogen atom or a methyl radical.

A particular value for R⁶ is a hydrogen atom or a methyl radical.

A particular value for the radical of the formula II is a2-methoxyethyl, 2-hydroxyethyl, 2-methylthioethyl or2-dimethylaminoethyl radical.

A particular value for the ring X is an oxazole, thiazole, imidazole,1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole,pyrazole, pyrazine, pyridine, pyrimidine or 1,3,5-triazine ring, eachbeing optionally substituted, where possible, by one or two substituentsselected from fluorine, chlorine and bromine atoms and methyl, methoxy,trifluoromethyl, hydroxy and amino radicals.

A particular value for --A-- is a phenylene, cyclopentylene,cyclohexylene, trimethylene, tetramethylene, pentamethylene,thioethylene, thiotrimethylene, thiotetramethylene, thiopentamethylene,oxyethylene, oxytrimethylene, oxytetramethylene, methylenethiomethylene,methylenethioethylene, methylenethiopropylene, methyleneoxymethylene,methyleneoxyethylene, ethyleneoxyethylene, oxy-2-methylethylene,thiopropylenethiomethylene, oxyethyleneoxymethylene, iminoethylene,iminopropylene, vinylenepropylene, oxymethylenevinylene, 1,3-phenylene,1,3-cyclopentylene, methylene-1,4-phenylene,ethyleneoxymethylene-1,4-phenylene, oxy-1,3-phenylenemethylene orthiomethyleneethynylenemethylene radical. These values for --A-- arewritten reading from left to right in formula I such that the firstnamed part of the radical is attached to ring X and the last named partof the radical is attached to C═D. Thus, for example, when --A-- is athiomethyleneethynylenemethylene radical, the compound of the formula Icontains the part structure III: ##STR3##

A particular value for R³ is a hydrogen atom or a hydroxy, amino,methylamino, 2,2,2-trifluoroethylamino, acetylamino, methyl, cyclohexyl,cyclohexylmethyl, allyl, propargyl, 2,2,2-trifluoroethyl, methoxy,2-hydroxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-aminoethyl,2-methylaminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl,2-benzoylaminoethyl, methoxycarbonylmethyl, 2-carbamoylpropyl, phenyl,benzyl, heteroaryl and heteroarylmethyl, in the latter two of which theheteroaryl part is a furan, thiophene, pyrrole, thiazole, oxazole,imidazole, thiadiazole, oxadiazole, triazole, pyrazole, pyridine orpyrimidine ring, and wherein when R³ is or contains a phenyl orheteroaryl ring, that ring is optionally substituted by one or twogroups selected from fluorine, chlorine, bromine and iodine atoms andmethyl, methoxy, methylthio, dimethylamino, acetyl, trifluoromethyl,hydroxy and amino radicals.

A particular value for the ring formed when R³ and R⁴ are joined is apyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazinering.

The following are 7 preferred features of the guanidine derivative ofthe formula I. When any one of these features is taken, either singly orin combination, with the other general or particular features of theguanidine derivative of the formula I listed above, there are obtainedpreferred sub groups of compounds within the above general definition.

1. R³ and R⁴ are hydrogen atoms.

2. R² is a hydrogen atom and R¹ is a 2,2,2-trifluoroethyl,2-chloro-2,2-difluoroethyl or 2,2,3,3-tetrafluoropropyl radical.

3. Ring X carries no optional substituent.

4. Ring X is a pyrazole, 1,2,3-triazole, 1,2,4-triazole in which A islinked at the 1-position, pyrimidine in which A is linked at the2-position, or thiazole in which A is linked at the 4-position, ring.

5. Ring X is a pyrazole, 1,2,3-triazole, or 1,2,4-triazole in which A islinked at the 1-position, ring.

6. Ring X is a pyrazole ring.

7. --A-- is a tetramethylene, pentamethylene, oxytrimethylene,oxytetramethylene, thiatrimethylene or thiatetramethylene radical.

Specific compounds of the invention are set out in the Examples. Thefollowing is a preferred group of compounds.

4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide(Example 6);

5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide (Example10);

5-[3-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrazol-1-yl]valeramide(Example 19);

5-[3-(2-[2-chloro-2,2-difluoroethyl]guanidino)pyrazol-1-yl]valeramide(Example 20),

5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]valeramide(Example 21);

5-[4-(2-[2,2,3,3-tetrafluoropropyl]guanidino)-1,2,3-triazol-2-yl]valeramide(Example 23);

6-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]hexanoamide(Example 24);

4-[4-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrimid-2-yloxy]butyramide(Example 44);

4-[2-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrid-6-ylthio]butyramide(Example 62);

and the pharmaceutically-acceptable acid-addition salts thereof.

Among this group of compounds, the compounds of Examples 10, 19 and 44are preferred and the compound of Example 10 is particularly preferred.

A suitable pharmaceutically-acceptable acid-addition salt of theguanidine derivative of the formula I is, for example, a salt formedwith hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, citric ormaleic acid.

The guanidine derivative of the invention may be manufactured by methodsin which the actual chemical reactions involved are known in themselves.The following processes, R¹, R², R³, R⁴, A, D and ring X having themeanings stated above, unless indicated otherwise, are thereforeprovided as further features of the invention.

The process of the invention is characterised by:

(a) reaction of a compound of the formula IV: ##STR4## or an activatedderivative thereof with a compund of the formula R³ R⁴ NH. The activatedderivative may, for example be an ester, for example a 1-6C ester, forexample a methyl or ethyl ester, or an acid halide, for example an acidchloride or acid bromide. Alternatively the activated derivative may bean anhydride, for example, a mixed anhydride. Particularly useful mixedanhydrides are those formed by reaction of the compound of the formulaIV with a chloroformate, for example ethyl chlorformate or isobutylchloroformate. The reaction may be conducted in a diluent or solventsuch as methanol, ethanol, methylene dichloride, tetrahydrofuran ordimethylformamide and the reaction may be accelerated or completed bythe application of heat, for example by heating to the boiling point ofthe diluent or solvent. When the activated derivative is an acid halideit is advantageous to conduct the reaction in the presence of a basesuch as triethylamine and to use a non-alcoholic diluent or solvent.

(b) for those compounds in which R³ and R⁴ are hydrogen atoms and D isan oxygen atom, hydrolysis of a compound of the formula V: ##STR5## Thehydrolysis is preferably carried out by use of a strong mineral acidsuch as concentrated sulphuric acid or by the use of hydrogen peroxidein a basic medium, for example in the presence of sodium hydroxide.

(c) construction of the guanidine radical attached to ring X by reactionof the appropriate thiourea, or a 1-6C S-alkyl (e.g. S-methyl) orS-benzyl derivative thereof, or a salt of such a derivative, with theappropriate amine. The guanidine radical in the compound of the formulaI contains three nitrogen atoms each of which carries differentsubstituents. The appropriate amine for use in this reaction maytherefore be ammonia, an amine of the formula R¹ R² NH or an amine ofthe formula VI: ##STR6## The reaction may be conducted using an excessof one of the reactants as a diluent or solvent, or an additionaldiluent or solvent, for example methanol or ethanol, may be added. Inmany cases it is advantageous to use a catalyst such as mercuric oxide,lead oxide or sodium hypochlorite. The reaction may be conducted atambient temperature or it may be accelerated or completed by theapplication of heat, for example by heating to the boiling point of thediluent or solvent.

(d) construction of the guanidine radical attached to ring X by reactionof the appropriate cyanamide with the appropriate amine. Since theguanidine radical in the compound of the formula I contains only oneunsubstituted nitrogen atom there are two appropriate amines, namely theamine of the formula R¹ R² NH or of the formula VI given above.

(e) for those compounds in which the group inserted into A is an oxygenor sulphur atom or an NH or N-alkyl radical, reaction of a compound ofthe formula VII or VIII: ##STR7## with a compound of the formula IX or Xrespectively: ##STR8## in which G is an oxygen or sulphur atom or an NHor N-alkyl radical, R⁷ is a displaceable radical and A¹ and A² arefragments of A, including direct bonds, and are such that A¹ --G--A²falls within the definition of A given above. R⁷ is, for example, ahalogen atom, for example a chlorine, bromine or iodine atom. When R⁷ isdirectly attached to ring X R⁷ may, for example, be a methylsulphinyl ormethylsulphonyl radical.

(f) for those compounds in which Z is a nitrogen atom, reaction of acompound of the formula XI: ##STR9## with a compound of the formula XII:##STR10## in which R⁷ is a displaceable radical. R⁷ is, for example, ahalogen atom, for example a chlorine, bromine or iodine atom.

(g) for those compounds in which ring X is a thiazole ring, reaction ofa compound of the formula XIII: ##STR11## with a compound of the formulaXIV: ##STR12## in which Hal is a chlorine or bromine atom and R⁸ is ahydrogen atom or the optional substituent on the thiazole ring. Thereaction may be conducted in a diluent or solvent such as acetone andmay be accelerated or completed by the application of heat, for exampleby heating to the boiling point of the diluent or solvent.

When the process of the invention manufactures the compound of theformula I in the form of the free base and an acid-addition salt isrequired, the compound of the formula I in the free base form is reactedwith an acid which affords a pharmaceutically-acceptable anion.

The starting material of the formula IV for use in process (a) may beobtained by separate construction of the two side chains on theappropriate ring X. Thus the left-hand side chain may be constructed byreduction of a nitro group to an amino group, reaction of this aminogroup with an isothiocyanate of the formula R¹ R² N═C═S, and finallyreaction of the resulting thiourea with ammonia in the presence ofmercuric oxide. The method of construction of the right hand side chainmay vary depending on the nature of ring X, the nature of the atom inring X to which A is attached (carbon or nitrogen) and the presence orabsence of inserted atoms or groups in chain A. In this construction itmay be necessary to protect the acid function as a cyano or ester groupand to hydrolyse to the acid as a final step. When A contains noinserted group or the inserted group is a phenylene radical and Z is acarbon atom, it is preferable to construct the ring X with the righthand chain already in place. Thus when ring X is a thiazole ring aprocess similar to that described in process (g) may be used, forexample as illustrated in Examples 51, 52, 53 and 54. When ring X is a1,2,3-triazole ring, it may be formed by reaction of methazonic acidwith a suitable azide, for example as illustrated in Example 26. Whenring X is a pyrimidine, it may be formed by reaction of a suitablysubstituted imino ether with 2-chloroacrylonitrile, for example asillustrated in Example 31. When the inserted group in A is vinylene orethynylene radical, A may be introduced by formation of the double ortriple bond by standard coupling methods, for example as illustrated inExample 48. When the inserted group in A is a cycloalkylene radical, thechain A may be constructed by a conjugate addition to the correspondingcycloalk-2-enone, for example as illustrated in Example 25. When theinserted group in A is an oxygen or sulphur atom or an NH or N-alkylradical, the right hand chain may be built up by a method similar tothat described in process (e), for example as illustrated in Examples 1,6, 29, 41, 47, 49, 56, 57, 59, 60, 61 and 62. When Z is a nitrogen atom,the right hand chain may be formed by a method similar to that describedin process (f), for example as illustrated in Examples 11, 21, 55 and58.

The starting material of the formula V for use in process (b) may beprepared by methods exactly analogous to the methods of preparation ofthe compound of the formula IV. Indeed, as already explained, thecompound of the formula V may be an immediate precursor of the compoundof the formula IV.

The starting material of the formula VI for use in process (c) may beprepared by the methods described above for the preparation of thecompounds of the formula IV or V in which the right hand chain isconstructed first, followed by use of one of the processes (a) or (b).

The cyanamide, corresponding to the amine of the formula VI, for use inprocess (d) may be prepared by reaction of the compound of the formulaVI with cyanogen bromide.

The starting materials of the formulae VII and VIII for use in process(e), and of the formula XI for use in process (f), may be prepared byconstruction of the guanidine chain on a suitably substituted ring X.

The starting material of the formula IV for use in process (a) is aparticularly useful intermediate for preparing the compounds of theformula I. This starting material, and the activated derivatives (1-6Calkyl ester, acid chloride, acid bromide, mixed anhydride) thereof andtherefore provided as a further feature of this invention. Particularlyuseful mixed anhydrides are those formed with 1-6C alkyl chloroformates,for example ethyl and isobutyl chloroformates.

The starting material of the formula V for use in process (b) is aparticularly useful intermediate for preparing the compounds of theformula I. This starting material is therefore provided as a furtherfeature of the invention.

As noted above, the guanidine derivative of the invention is a histamineH-2 antagonist, inhibits the secretion of gastric acid in warm-bloodedanimals and is therefore useful in the treatment of peptic ulcers andother conditions caused or exacerbated by gastric acidity, includingstress ulcers and gastrointestinal bleeding due to trauma.

The histamine H-2 antagonist activity may be demonstrated on standardtests, for example by the ability of the compound of the formula I toinhibit the histamine-induced positive chronotropic response in thespontaneously beating right atrium of the guinea pig or by its abilityto inhibit the histamine-induced uptake of aminopyrine into the acidspace of parietal cells.

The guinea pig atrium test is carried out as follows:

A guinea pig right atrium is suspended at 1 g. tension (isometric) in athermostatically-controlled (30° C.) tissue bath (25 ml.) containingoxygenated (95% O₂,5% CO₂) Krebs-Henseleit buffer (pH 7.4). The tissueis allowed to stabilise over 1 hour during which time it is washed 2-4times. Individual contractions are recorded with a force-displacementtransducer through a strain gauge coupler, and instantaneous rates aremonitored with a cardiotachometer. A control response to 1 μM histamineis obtained after which the tissue is washed 3 times and allowed tore-equilibrate to basal rate. After re-equilibration for 15 minutes, thetest compound is added to the desired final concentration. Ten minutesafter addition of the compound histamine (1 μM) is again added and theresponse to histamine in the presence of antagonist is compared to thehistamine control response. The result is expressed as a percentage ofthe histamine control response. Thereafter the apparent dissociationconstant of the H-2 antagonist is determined by standard procedures.

The aminopyrine test is carried out as follows:

Gastric mucosa from the New Zealand white rabbit is removed from theunderlying muscle and washed in Buffer 1 [containing per liter NaCl;(8.007 g.), KCl (0.201 g.), Na₂ HPO₄ (0.113 g.), KH₂ PO₄ (0.204 g.),CaCl₂.2H₂ O (0.132 g.), MgCl₂ (0.101 g.) and glucose (1 g.), adjusted topH 7.4 with NaOH]. The tissue is finely chopped, suspended in Buffer 1and washed three times with Buffer 1. The tissue is then suspended indispersion medium [collagenase (Sigma Chemical Co., Type V; 100 mg.) andbovine serum albumin (Miles Laboratories Ltd., Fraction V; 100 mg.) inBuffer 1 (100 ml.); 50 ml. per 10 g. net weight of tissue] and incubatedat 30° C. and pH 7.4 (maintained by continuous monitoring) with stirringunder an oxygen atmosphere. After 30 minutes the tissue is allowed tosettle and the supernatant liquid is removed. Fresh dispersion medium(50 ml. per 10 g. wet weight of tissue) is added and incubation iscontinued with the tissue being largely dispersed into glands and wholecells after 40-60 minutes. Any remaining large pieces of tissue areremoved by filtration through nylon mesh. The mixture of glands andcells is collected by centrifugation at 200×g and suspended in Buffer 1containing 1% bovine serum albumin (Miles Laboratories Ltd., FractionV). Finally the cells and glands are washed 3 times with Buffer 1 andsuspended in Buffer 2 [containing Eagles MEM (500 ml.), Aprotinin (SigmaChemical Co., 10 mg.) and HEPES(2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulphonic acid; 150 mM., 20ml.) adjusted to pH 7.4 with NaOH; 150 ml. per 10 g. net weight oftissue]. The tissue suspension is stirred under an oxygen atmosphere at32° C. for at least 1 hour before use. The tissue suspension isincubated with the test compound and aminopyrine (10 μM) labelled withC¹⁴ on the dimethylamino group (0.1 μCi/ml.) for 20 minutes. The uptakeof the aminopyrine is then stimulated by addition of histamine and thephosphodiesterase inhibitor ICI 63197 (Eiochem. Soc. Special Publication1, 1973, pp 127-132) to final concentrations of 10⁻⁵ M. and 5×10⁻⁷ M.respectively. After 18 minutes the cells/glands are separated from theincubation medium by filtration of the suspension through glassmicrofibre filters. The cells/glands are quickly (<10 seconds) washedthree times with ice-cold Buffer 1. The C¹⁴ aminopyrine retained by thetissue is measured on a scintillation counter and the degree ofinhibition of uptake by the test compound is calculated by reference toa control sample. The concentration of test compound giving 50%inhibition is then calculated graphically from a series of tests run atdifferent concentrations.

All the compounds exemplified in this specification were tested eitheron the guinea pig atrium test or on the aminopyrine test. All thosetested on the guinea pig atrium test are active at or below a bathconcentration of 10 μM. and the more active compounds show completeinhibition of response at this concentration. All those tested on theaminopyrine test gave a 50% inhibition of uptake of aminopyrine at orbelow a concentration of 3 μM.

The inhibition of the secretion of gastric acid may be demonstrated instandard tests, for example by the ability of the compound of theformula I, when dosed intravenously, intragastrically or orally, toinhibit the secretion of acidic gastric juice in, for example, rats, ordogs provided with gastric fistulae or denervated fundic pouches, andwhose gastric secretion is stimulated by administration of asecretagogue, for example histamine, pentagastrin, bethanechol or food.

The test in rats is carried out as follows:

Female rats (200-230 g.) are anesthetized by intramuscularadministration of urethane (1.5 g/kg.) and the trachea cannulated. Asoft tube is passed down the oesophagus into the stomach and secured bya tie in the neck region. A multi-orifice plastic tube (3 mm. diameter)is passed into the antral region of the stomach, via an incision in theduodenum, and tied in place by means of a ligature around the pylorus.Saline (9 g./l. NaCl) is perfused through the stomach via theoesophageal cannula at a rate of 7 ml./minute and collected into beakersfrom the pyloric outlet over periods of 10 minutes. Acid secretion isstimulated by subcutaneous administration of the specific H-2 agonistdimaprit in a loading dose of 10 mg./kg. followed by an infusion of 30mg./kg./hour. Acid output is computed by titration of the 10 minutesamples to an end point of pH 6.4 with 20 mM. NaOH. When secretion hasreached a plateau (three consecutive readings within 5%) the testcompound is administered intravenously via a cannula placed in the leftexternal jugular vein. Secretion is then measured for a further 2 hours.A stock solution of each test compound is prepared (10 mg./ml. in DMSO)and appropriate dilution made with saline to enable injection in a dosevolume of 1 ml./kg. (DMSO<2%).

The test in dogs provided with chronic fistulae is carried out asfollows:

A female pure bred beagle (9-12 kg.) having a chronic gastric fistula isfasted overnight with water ad lib. During the experiment the dog islightly restrained in a standing position. When studying the testcompound by the intravenous route, the fistula is opened and, afterascertaining the absence of basal secretion over a period of 30 minutes,a continuous intravenous infusion of secretagogue (0.5 μmol./kg./hour ofhistamine or 2 μg./kg./hour pentagastrin) in saline (15 ml./hour) isbegun. Gastric acid samples are collected every 15 minutes. The volumeof each sample is measured and a 1 ml. aliquot is titrated to neutralitywith 100 mM NaOH to determine acid concentration. When a plateau ofsecretion is reached (1-2 hours), the test compound is administeredintravenously in saline and gastric acid samples are collected for afurther 2-3 hours during which time the infusion of the secretagoguecontinues uninterrupted.

When studying the test compound by the intragastric route, the absenceof basal secretion over a period of 30 minutes is ascertained and thetest compound, contained in 25 ml. of 0.5% w/v hydroxypropylmethylcellulose and 0.1% w/v `Tween` 80 in water (`Tween` is a TradeMark) is instilled into the stomach through a fistula dosing plug. Onehour later, the fistula is reopened and intravenous infusion of asecretagogue, as described above, is immediately begun. Gastric acidsamples are measured as described above and the approach of acidsecretion to a plateau is compared to that of a control animal which isdosed intragastrically only with the dosing vehicle.

When studying the test compound by the oral route it is administered ina gelatin capsule with 15 ml. of water. One hour later, the fistula isopened and intravenous infusion of the secretagogue is immediatelybegun. Gastric acid samples are measured as above and the approach ofacid secretion to a plateau is compared to that of an undosed controlanimal.

The test in dogs provided with denervated fundic pouches is carried outas follows:

Male beagle dogs (14-22 kg.) are prepared with vagally denervatedpouches of the fundic gland area by the method of Rudick et al. (J.Surg. Res. 1967, 7 383.) The animals are allowed 4-6 weeks to recoverfrom surgery and a further period of 2-3 months prior to routine use, toallow for table training and standardization of secretory responses. Thedogs are starved for 23 hours before use (water ad lib) and duringexperiments they are lightly restrained in cloth slings. After rinsingthe pouch with warm water, histamine is infused subcutaneously at a rateof 10 μg./minute. This dose of agonist produces a submaximal (60-90% ofmaximum) increase in acid output in all dogs used. Pouch secretions arecollected over 15 minute periods into graduated glass test-tubes and thevolume measured to the nearest 0.1 ml. A 500 μl sample is diluted with 5ml. of saline and titrated to pH 7.0 with 100 mM. NaOH. Total acidoutput is computed from the product of acid concentration and volume ofjuice secreted. Compounds are administered intravenously (0.1 ml./kg.)via a cephalic vein or orally in a gelatin capsule when a secretoryplateau (3 consecutive readings within 10%) has been attained. Secretionis measured for a period of 3 hours following administration of testcompound.

The results obtained in the atrium and aminopyrine tests are predictiveof activity in the rat and dog tests.

No overt toxicity or side effects were noted during the rat or dogtests. The compounds5-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)valeramide,5-(4-[2-(2,2,2-trifluoroethyl)guanidino]-1,2,3-triazol-2-yl)valeramide,5-(6-[2-(2,2,3,3-tetrafluoropropyl)guanidino]pyrid-2-yl)valeramide and5-(3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl)valeramide wereadministered intravenously to groups of two anaesthetised rats and fourconscious mice at doses which were respectively ten times and onehundred times the dose, in mg./kg., which produced an approximate 50%inhibition of gastric secretion in the anaesthetised rat. No toxicsymptoms were noted in any of the dosed animals.

A number of compounds exemplified in this specification exhibitinhibition of acid secretion which shows little or no decline from peakinhibition for several hours.

The N-methylcyanoguanidine group in known H-2 receptor antagonists ispotentially changeable into the carcinogenic N-nitrosoN-methylcyanoguanidine group in the mammalian body (Pool et al.,Toxicology, 1979, 15, 69). The corresponding group in the compounds ofthe present invention, CONR³ R⁴, is not potentially changeable intocarcinogenic nitroso derivatives when R³ and R⁴ are hydrogen atoms.

According to a further feature of the invention there is provided apharmaceutical composition which comprises an guanidine derivative ofthe invention in association with a non-toxicpharmaceutically-acceptable diluent or carrier.

The pharmaceutical composition may, for example, be in a form suitablefor oral, rectal, parenteral or topical administration, for whichpurposes it may be formulated by means known to the art into the formof, for example, tablets, capsules, aqueous or oily solutions orsuspension, emulsions, dispersible powders, suppositories, sterileinjectable aqueous or oily solutions or suspensions, gels, creams,ointments or lotions.

In addition to the guanidine derivative of the formula I, thepharmaceutical composition of the invention for oral, rectal orparenteral administration may also contain, or be co-administered with,one or more known drugs selected from antacids, for example aluminiumhydroxide--magnesium hydroxide mixtures; antipepsin compounds, forexample pepstatin; other histamine H-2 antagonists, for examplecimetidine or ranitidine; ulcer healing agents, for examplecarbenoxolone or bismuth salts; anti-inflammatory agents, for exampleibuprofen, indomethacin, naproxen or aspirin prostaglandins, for example16,16-dimethylprostaglandin E₂ ; classical antihistamines (histamine H-1antagonists), for example mepyramine or diphenhydramine; anticholinergicagents, for example atropine or propantheline bromide; anxiolyticagents, for example diazepam, chlorodiazepoxide or phenobarbital.

The pharmaceutical composition of the invention for topicaladministration may also contain, in addition to the guanidinederivative, one or more classical anti-histamines (histamine H-1antagonists), for example mepyramine or diphenhydramine and/or one ormore steroidal anti-inflammatory agents, for example fluocinolone ortriamcinolone.

A topical formulation may contain 1-10% w/w of the guanidine derivativeof the invention. A preferred pharmaceutical composition of theinvention is one suitable for oral administration in unit dosage form,for example a tablet or capsule which contains between 5 mg. and 500 mg.of the guanidine derivative, or one suitable for intravenous,subcutaneous or intramuscular injection, for example a sterileinjectable containing between 0.1% and 10% w/w of the guanidinederivative.

The pharmaceutical composition of the invention will normally beadministered to man for the treatment of peptic ulcers and otherconditions caused or exacerbated by gastric acidity in the same generalmanner as that employed for cimetidine, due allowance being made interms of dose levels for the potency and duration of action of theguanidine derivative of the present invention relative to cimetidine.Thus each patient will receive an oral dose of between 5 mg. and 500mg., and preferably between 10 mg. and 100 mg., of guanidine derivativeor an intravenous, subcutaneous or intramuscular dose of between 0.5 mg.and 50 mg., and preferably between 2 mg. and 20 mg., of the guanidinederivative, the composition being administered 1 to 4 times, andpreferably once, per day. The rectal dose will be approximately the sameas the oral dose. The composition may be administered less frequentlywhen it contains an amount of guanidine derivative which is a multipleof the amount which is effective when given 1-4 times per day.

The invention is illustrated, but not limited, by the followingExamples. The n.m.r. spectra are quoted in δ relative totetramethylsilane (δ=0) as internal standard (s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, br=broad). The temperatures are indegrees Centigrade. The following contractions are used:

    ______________________________________                                        HOAc      =            acetic acid                                            DMF       =            dimethyl formamide                                     ether     =            diethyl ether                                          DMSO      =            dimethylsulphoxide                                     MeOH      =            methanol                                               EtOH      =            ethanol                                                THF       =            tetrahydrofuran                                        EtOAc     =            ethyl acetate                                          ______________________________________                                    

Attention is drawn to the fact that 3-nitropyrazole (Examples 10, 11 and58) and 4-nitrotriazole (Example 21) are both explosion hazards. In theExamples and thoughout the specification, the following abbreviationsare used: C,H,N,O. etc. (The conventional chemical symbols for theelements unless otherwise designated).

EXAMPLE 1

A mixture of ethyl4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyramid-2-ylthio]butyrate (0.18g.) and a 33% w/v solution of methylamine in EtOH (5 ml.) was stirred atroom temperature for 4 days and then evaporated to dryness. The residuewas recrystallised from EtOAc to giveN-methyl-4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide(0.09 g.), m.p. 153°-155°.

The ester used as starting material in the above process may be preparedas follows:

A mixture of 2-thiocytosine (0.64 g.), ethyl 4-bromobutyrate (1.07 g.)and 1,5-diazabicyclo[5,4,0]undec-5-ene (0.84 g.) was stirred for 4 hoursand then evaporated to dryness. The residue was treated with water andthe mixture extracted with EtOAc, and the extract dried and evaporatedto dryness to give a gum (1.9 g.). The gum was dissolved in acetonitrile(5 ml.) the solution treated with 2,2,2-trifluoroethyl isothiocyanate(1.1 g.) and the mixture heated at 70° for 72 hours with the addition offurther portions of isothiocyanate (0.5 g.) at 24 and 48 hours. Themixture was cooled and the solid which crystallised was collected togive ethyl4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyrate, m.p.104°-106°.

A mixture of ethyl4-[4-(3-[2,2,2-trifluoroethylthioureido)pyrimid-2-ylthio]butyrate (0.25g.), DMF (2 ml.), saturated ethanolic ammonia (5 ml.) and yellowmercuric oxide (0.2 g.) was stirred at room temperature for 2 hours andthen filtered. The filtrate was evaporated to dryness and the residuerecrystallised from EtOAc to give ethyl4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate, m.p.120°-122°.

EXAMPLE 2

A mixture of ethyl4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (0.2g.), ethanolamine (0.5 ml.) and MeOH (5 ml.) was heated under reflux for48 hours and then evaporated to dryness. Water was added to the residue,and the mixture extracted with EtOAc. The extract was dried andevaporated to dryness and the residue recrystallised from a small volumeof EtOAc to giveN-(2-hydroxyethyl)-4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide(0.12 g.), m.p. 148°-150°.

EXAMPLE 3

A mixture of ethyl4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (0.2g.), ethylenediamine (2 ml.) and MeOH (5 ml.) was kept at roomtemperature for 18 hours and then heated under reflux for 4 hours. Thesolution was evaporated to dryness, the residue treated with water, andthe mixture extracted with EtOAc. The extract was dried and evaporatedto dryness. The residue was dissolved in acetone and the solution addedto a solution of maleic acid in acetone. The precipitate was collectedto giveN-(2-aminoethyl)-4-[4-(2-[2,2,2-trifluoroethyl]-guanidino)pyrimid-2-ylthio]butyramidebis hydrogen maleate (0.22 g.), m.p. 144°-148°.

EXAMPLE 4

By a similar process to that in Example 1, using ethyl5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2 ylthio]valerate(prepared in an analogous manner to the butyrate used in Example 1)there was obtainedN-methyl-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]valeramide,m.p. 148°-150°.

EXAMPLE 5

By a similar process to that described in Example 2 using ethyl5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]valerate asstarting material there was obtainedN-(2-hydroxyethyl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]valeramidehydrogen maleate, m.p. 179°-181°.

EXAMPLE 6

A mixture of4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile(0.14 g.) and concentrated H₂ SO₄ was left at room temperature for 3hours and then diluted with crushed ice and water. The solution wasbasified with 10 N aqueous NaOH and the mixture extracted three timeswith EtOAc. The combined extracts were dried and evaporated to drynessto give4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide(0.13 g.) which was characterised as the hydrogen maleate, m.p.202°-203° on recrystallisation from aqueous EtOH.

The starting material for use in the above process may be prepared asfollows:

4-Chlorobutyronitrile (0.23 g.) in EtOH (2 ml.) was added to a solutionof 2-thiocytosine (0.25 g.) in 0.5 N aqueous NaOH (5 ml.) and themixture stirred for 18 hours. A further portion of 4-chlorobutyronitrile(0.23 g.) was added and the mixture stirred a further 24 hours. Thesolution was concentrated in vacuo to 2 ml. and cooled and thecrystalline precipitate collected to give4-[4-aminopyrimid-2-ylthio]butyronitrile (0.3 g.), m.p. 99°-100°.

A mixture of 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.25 g.),acetonitrile (3 ml.) and 2,2,2-trifluoroethyl isothiocyanate (0.21 g.)was stirred at 70° for 72 hours and then evaporated to dryness. Theresidue was crystallised from a mixture of ether and petroleum ether(b.p. 60°-80°) to give4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile(0.37 g.), m.p. 125°-126°.

A mixture of4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile(0.32 g.), saturated ethanolic ammonia (20 ml.) and yellow mercuricoxide (0.5 g.) was stirred at room temperature for 20 hours and thenfiltered and the filtrate evaporated to dryness. The residue wasrecrystallised from a mixture of acetone and petroleum ether (b.p.60°-80°) to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid- b2-ylthio]butyronitrile (0.29 g.), m.p. 137°.

EXAMPLES 7 AND 8

By a similar process to that described in Example 6 and using theappropriate nitrile (prepared in an analogous manner to thebutyronitrile described in Example 6) as starting material, there wereobtained5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]valeramidehydrogen maleate, m.p. 184°-186° and6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]hexanoamidehydrogen maleate, m.p. 176°-177°.

EXAMPLE 9

A mixture of4-(4-[2-(2-methoxyethyl)guanidino]pyrimid-2-ylthio)butyronitrile (0.16g.) and concentrated sulphuric acid (2 ml.) was stirred at ambienttemperature for 5 hours. The reaction mixture was then cooled in anice-bath and basified by careful dropwise addition of concentratedaqueous ammonia (s.g. 0.880). The resulting white precipitate wascollected, washed with water and then cold EtOH. The solid was dissolvedin hot EtOH with maleic acid and the solution allowed to cool. There wasthus obtained4-(4-[2-(2-methoxyethyl)guanidino]pyrimid-2-ylthio)butyramide maleate(0.22 g.), m.p. 194°-195°.

The starting material may be obtained as follows:

To a stirred mixture of 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.60g.) and tetrahydrofuran (30 ml.) under argon at -78° was added n-butyllithium (1.6 molar in hexane; 1.9 ml.). The reaction mixture was stirredfor 0.5 hours at -78° and then 2-methoxyethylisothiocyanate (0.35 g.) intetrahydrofuran (5 ml.) was added dropwise. The reaction mixture wasallowed to warm to ambient temperature and stirring was continued for afurther 64 hours. The reaction was poured into water and extracted (×3)with EtOAc. The combined extracts were evaporated to dryness to give acrude solid which was purified by medium pressure chromatography onsilica using CHCl₃ /MeOH 9.5:0.25 v/v as eluant. The purified product(0.25 g.) was immediately added to a stirred mixture of EtOh saturatedwith ammonia (10 ml.) and mercuric oxide (0.22 g.) and stirring wascontinued for 1.5 hours. The reaction mixture was filtered throughdiatomaceous earth, the filtrate evaporated and the residue purified bymedium pressure chromatography on silica using CHCl₃ /MeOH/aqueousammonia (s.g. 0.880) 9.5:0.6:0.05 v/v/v as eluant to give4-(4-[2-(2-methoxyethyl)guanidino]pyrimid-2-ylthio)butyronitrile (0.16g.) as a semicrystalline solid which was used without furtherpurification.

EXAMPLE 10

5-[3-(2-[2,2,2-Trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile (13g.) was added over 10 minutes to concentrated sulphuric acid (65 ml.)with stirring. The resulting solution was kept at 20° for 18 hours thendiluted with ice (300 ml.) and basified to pH 9 with 10.8 N sodiumhydroxide. The mixture was extracted with EtOAc (3×200 ml.) and theextract was dried (MgSO₄) and evaporated in vacuo to an oil whichcrystallised. The crude material was recrystallised from EtOAc to give5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p.130°. The maleic acid salt was prepared in acetone, m.p. 183°-184°.

The starting material may be prepared as follows:

Sodium hydride paste (6.16 g. of 61% w/w suspension in liquid paraffin)was added portionwise over 30 minutes to a solution of 3-nitropyrazole(17.4 g.) in dry DMF (150 ml.) with external ice cooling to maintain thetemperature at 20°-30°. The mixture was stirred for 45 minutes and tothe almost clear solution was added 5-bromovaleronitrile (25 g.) over 30minutes, at 25°-30°, and the mixture was stirred for 4 hours. Water (450ml.) and EtOAc (450 ml.) was added and the upper layer was separated,dried (MgSO₄) and evaporated in vacuo to an oil which was a mixture of5-(3-nitropyrazol-1-yl)valeronitrile and5-(5-nitropyrazol-1-yl)valeronitrile. The oil was divided into two 15 g.portions which were fractionated on a silica column (3.5 cm diameter×100cm long) eluted at 2 atmospheres by EtOAc/60°-80° petroluem ether (3:7v/v). The 1.5 isomer was eluted first followed by the 1:3 isomer. The5-(3-nitropyrazol-1-yl)valeronitrile had m.p. 32°-33°.

To a solution of 5-(3-nitropyrazol-1-yl)valeronitrile (9.16 g.) in drytetrahydrofuran (200 ml.) was added 5% w/w palladium on carbon (1.8 g.).The mixture was stirred at 20° under an atmosphere of hydrogen. 3.2Liters of hydrogen were absorbed over 4 hours. The catalyst was filteredoff and the filtrate was evaporated in vacuo to give5-(3-aminopyrazol-1-yl)valeronitrile as an oil.

To a solution of 5-(3-aminopyrazol-1-yl)valeronitrile (7.0 g.) inacetonitrile (25 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6.02g.). After 15 minutes the solvent was evaporated in vacuo to give5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeronitrile as awhite crystalline solid, m.p. 96°-98°.

The above thiourea (12.5 g.) was dissolved in 8 M ammonia in EtOH (120ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at20° for 30 minutes. The resulting mixture was filtered and the filtratewas evaporated in vacuo to give5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile as anoil. A sample of the oil was dissolved in acetone and 5 molecularequivalents of maleic acid was added. Ether was added to the resultingclear solution to produce the crystalline maleate, m.p. 123°-125°.

Alternatively, the5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile maybe prepared by reaction of 3-aminopyrazole with2,2,2-trifluoroethylisothiocyanate, reaction of the resulting thioureawith ammonia in the presence of mercuric oxide and finally alkylation ofthe nitrogen atom in the 1-position of the product,3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole, with5-bromovaleronitrile.

EXAMPLE 11

To a solution of5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide (0.5g.) in 6 M ammonia in ethyl alcohol (6 ml.) was added mercuric oxide(0.56 g.) over 5 minutes. The mixture was stirred for 1 hour andfiltered. The filtrate was evaporated in vacuo to an oil which wasdissolved in EtOAc. Addition of petroleum ether (b.p. 60°-80°) gave5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide as acrystalline solid, m.p. 128°-132°.

The starting material may be obtained as follows:

A solution of 5-(3-nitropyrazol-1-yl)valeronitrile (0.2 g.) inconcentrated sulphuric acid (1 ml.) was kept at 20° for 19 hours. Themixture was diluted with water (4 ml.), basified to pH 10 with 10.8 Nsodium hydroxide and extracted with EtOAc (3×5 ml.). The extracts weredried (MgSO₄) and evaporated in vacuo to a white solid which wasrecrystallised from ethanol to give 5-(3-nitropyrazol-1-yl)valeramide,m.p. 129°-131°.

A mixture of 5-(3-nitropyrazol-1-yl)valeramide (3.6 g.) and 3% w/wpalladium on carbon (0.54 g.) was stirred in isopropanol (20 ml.) underan atmosphere of hydrogen. The temperature was kept below 40° byexternal ice cooling. After 4 hours no more hydrogen was absorbed. Themixture was filtered and the filtrate was evaporated in vacuo to give5-(3-aminopyrazol-1-yl)valeramide as an oil which crystallised. Thisproduct (2.5 g.) was stirred in acetonitrile (25 ml.) and2,2,2-trifluoroethylisothiocyanate (2.17 g.) was added. After 18 hoursthe mixture was filtered and the residue was washed with acetonitrilethen ether to give5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide, m.p.172°-174°.

EXAMPLE 12

To a solution of 2,2,2-trifluoroethylcyanamide (0.65 g.) and5-(3-aminopyrazol-1-yl)valeramide (0.87 g.) in EtOH (10 ml.) was addedconcentrated hydrochloric acid (5 drops). The resulting mixture washeated under reflux for 5 hours. During this period drops ofconcentrated hydrochloric acid were added perodically to maintain the pHat 4. Volatile material was evaporated in vacuo and the residue wasshaken with 2 N aqueous sodium hydroxide (10 ml.) and EtOAc (35 ml.).The organic layer was separated and the aqueous phase was re-extractedwith EtOAc (2×35 ml.). The combined extracts were dried (MgSO₄) andmaleic acid dissolved in acetone was added to give5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide maleate,m.p. 180°-182°.

The 2,2,2-trifluoroethylcyanamide used as starting material may beobtained as follows:

Cyanogen bromide (1.06 g.) was dissolved in cold ether (5 ml.) and addedto a solution of 2,2,2-trifluoroethylamine (1.98 g.) in cold ether (5ml.). The mixture was allowed to warm to 20° over 30 minutes thenfiltered. The residue was washed with ether and the combined filtrateswere evaporated in vacuo at 20° to give 2,2,2-trifluoroethylcyanamide asa mobile oil which solidified on storage at -15°. The i.r. spectrumshowed a band at 2280 cm⁻¹ (--CN). The n.m.r. spectrum in d₄ methanolwith tetramethylsilane as an internal standard (δ=0) had the followingresonance: (δ) 3.65 (quartet).

EXAMPLE 13

The process of Example 1 was repeated, using hydrazine in place ofmethylamine, to obtain4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyric acidhydrazide, m.p. 192°-195°.

EXAMPLES 14-16

The process described in Example 29 was repeated, using4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyric acidand the appropriate amines as starting materials. The followingcompounds were thus obtained:

    ______________________________________                                         ##STR13##                                                                    Example           R                                                           ______________________________________                                        14                CF.sub.3 CH.sub.2                                           15                                                                                               ##STR14##                                                  16                OCH.sub.3                                                   ______________________________________                                    

Notes

Example 14: maleate, m.p. 202°-204° (yield 50%).

Example 15: m.p. 176°-178° (yield 47%).

Example 16: maleate, m. p. 161°-163° (yield 15%).

The starting material may be prepared as follows:

A mixture of ethyl4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyramid-2-ylthio]butyrate (1.03g.) and a solution of sodium hydroxide (0.13 g.) in water (10 ml.) washeated under reflux for 1 hour and then cooled. The solution wasacidified with glacial HOAc and the white solid which crystallised wascollected to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyric acid (0.75 g.), m.p. 234°-236°.

EXAMPLES 17-20

The process of Example 10 was repeated, using the appropriate startingmaterials, to obtain the following compounds.

    ______________________________________                                         ##STR15##                                                                    Example       R            m                                                  ______________________________________                                        17            CF.sub.3 CH.sub.2                                                                          3                                                  18            CF.sub.3 CH.sub.2                                                                          5                                                  19            CHF.sub.2 CF.sub.2 CH.sub.2                                                                4                                                  20            CClF.sub.2 CH.sub.2                                                                        4                                                  ______________________________________                                    

Notes

Example 17: 1.25 maleate, m.p. 158°-159° (yield 36%).

Example 18: 1.5 maleate, m.p. 130°-131° (yield 41%).

Example 19: 2 maleate 0.5 H₂ O, m.p. 93°-95° (yield 58%).

Example 20: 1.25 maleate, m.p. 162°-163° (yield 86%).

The starting materials may be prepared by repeating the second, third,fourth and fifth parts of Example 10 using, where appropriate,4-bromobutyronitrile or 6-bromohexanonitrile in place of5-bromovaleronitrile and using, where appropriate,2,2,3,3-tetrafluoropropylisothiocyanate or2-chloro-2,2-difluoroethylisothiocyanate in place of2,2,2-trifluoroethylisothiocyanate.

EXAMPLE 21

A solution of5-[(4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]valeronitrile(0.35 g.) in concentrated sulphuric acid (1.0 ml.) was kept at roomtemperature for 5 hours. The mixture was poured into ice water (5 ml.),basified with aqueous NaOH, saturated with NaCl and extracted withEtOAc. The extract was dried (MgSO₄) and evaporated to give a yellowgum. This gum was dissolved in a small volume of EtOAc and treated witha solution of maleic acid (0.14 g.) in a small volume of acetone to givea solution from which the product crystallised. The product was filteredto give 0.33 g. of5-[4-(2-[2,2,2-trifluoroethylguanidino)-1,2,3-triazol-2-yl]valeramidemaleate, m.p. 156°-157°.

The starting material may be obtained as follows:

A stirred solution of 4-nitro-1,2,3-triazole (23.0 g.) in dry DMF (135ml.) was treated at room temperature with a dispersion of sodium hydride(4.8 g.) in mineral oil (4.8 g.). The mixture was stirred for 30 minutesand then treated with 5-bromovaleronitrile (33.0 g.). The mixture wasstirred overnight at room temperature and then poured into water. Theproduct was extracted into EtOAc and purified by column chromatographyon silica gel (1 kg.) eluted with EtOAc/petroleum ether (b.p. 60°-80°)(1:1 v/v) to give 22.3 g. of5-(4-nitro-1,2,3-triazol)-2-yl)valeronitrile as an oil.

A suspension of palladium on charcoal (5% w/w; 0.5 g.) in a solution of5-(4-nitro-1,2,3-triazol-2-yl)valeronitrile (1.0 g.) in acetic acid (20ml.) was stirred under one atmosphere of hydrogen until 420 ml. ofhydrogen had been absorbed. The mixture was filtered and evaporated togive 0.85 g. of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile as an oil.

A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (0.35 g.) and2,2,2-trifluoroethylisothiocyanate (0.5 g.) in acetonitrile (5 ml.) wasstirred at room temperature overnight. The mixture was evaporated andthe residue recrystallised from toluene/petroleum ether (b.p. 60°-80°)to give 0.5 g. of5-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]valeronitrile,m.p. 86°-88° after recrystallisation from toluene.

A stirred solution of5-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]valeronitrile(0.45 g.) in ammoniacal EtOH (6 M; 10 ml.) was treated at roomtemperature with mercuric oxide (0.6 g.). The mixture was stirred atroom temperature for 2 hours. The mixture was filtered and evaporated togive 0.41 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl)valeronitrile.

EXAMPLES 22-24

The process of Example 21 was repeated, using the appropriate startingmaterials, to obtain the following compounds.

    ______________________________________                                         ##STR16##                                                                    Example       R            p                                                  ______________________________________                                        22            CF.sub.3 CH.sub.2                                                                          3                                                  23            CHF.sub.2 CF.sub.2 CH.sub.2                                                                4                                                  24            CF.sub.3 CH.sub.2                                                                          5                                                  ______________________________________                                    

Notes

Example 22: maleate, m.p. 159°-161° (yield 53%).

Example 23: maleate, m.p. 141°-142° (yield 58%).

Example 24: maleate, m.p. 146°-147° (yield 49%).

The starting materials may be prepared by repeating the second, third,fourth and fifth parts of Example 21 using, where appropriate,4-bromobutyronitrile or 6-bromohexanonitrile in place of5-bromovaleronitrile, and using, where appropriate,2,2,3,3-tetrafluoropropylisothiocyanate in place of2,2,2-trifluoroethylisothiocyanate.

EXAMPLE 25

A mixture of3-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]cyclopentanecarboxamide(0.34 g.), mercuric oxide (0.4 g.) and methanolic ammonia (6 M; 20 ml.)was stirred at room temperature for 3 hours. The mixture was kept atroom temperature overnight, filtered, and evaporated to give 0.27 g. of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]cyclopentanecarboxamide.A sample in a small volume of EtOAc was treated with an equivalent ofmaleic acid in a small volume of acetone to give, on addition of ether,3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]cyclopentanecarboxamidemaleate, m.p. 143°-146°.

The starting material may be prepared as follows:

A mixture of 1,2,3-triazole (3.5 g.), cyclopent-2-enone (5.0 g.),benzyltrimethylammonium hydroxide (40% w/v solution in MeOH; 2.0 ml.)and dioxan (20 ml.) was stirred at room temperature overnight. Themixture was evaporated, treated with EtOAc, washed twice with water andonce with brine, dried (MgSO₄), and evaporated to give unpurified3-(1,2,3-triazol-2-yl)cyclopentanone as a pale yellow oil. The n.m.r.spectrum of the product exhibited the following resonances: 7.62 (s,2H); 5.37 (br quintet, 1H); 3.1-1.8 (m, 6H). (solvent CDCl₃)

A mixture of unpurified 3-(1,2,3-triazol-2-yl)cyclopentanone (0.5 g.),lithium aluminium hydride (0.5 g.) and ether (20 ml.) was stirred atroom temperature overnight. The excess of lithium aluminium hydride wasdestroyed with aqueous NaOH. The reaction mixture was filtered andevaporated to give 0.5 g. of unpurified3-(1,2,3-triazol-2-yl)cyclopentanol as an oil.

A solution of unpurified 3-(1,2,3-triazol-2-yl)cyclopentanol (0.44 g.)in pyridine (5 ml.) was treated at 5° with toluene-p-sulphonyl chloride(1.1 g.). The mixture was kept at 5° overnight and then poured intowater and extracted with EtOAc. The extract was washed with water,aqueous HCl (2 N) and brine, and then dried (MgSO₄), and evaporated togive 0.72 g. of unpurified 3-(1,2,3-triazol-2-yl)cyclopentyltoluene-p-sulphonate as an oil.

A mixture of unpurified 3-(1,2,3-triazol-2-yl)cyclopentyltoluene-p-sulphonate (0.7 g.), NaCN (0.17 g.) and DMSO (10 ml.) wasstirred at 95° overnight. The mixture was poured into water andextracted with EtOAc. The extract was washed with brine, dried (MgSO₄),and evaporated to give 0.33 g. of unpurified3-(1,2,3-triazol-2-yl)cyclopentanecarbonitrile as an oil.

A mixture of unpurified 3-(1,2,3-triazol-2-yl)cyclopentanecarbonitrile(0.3 g.), concentrated sulphuric acid (2 ml.), and concentrated nitricacid (1 ml.) was kept at room temperature overnight. The initialreaction was exothermic and required cooling. The mixture was pouredinto water and extracted with EtOAc. The extract was washed with brine,dried (MgSO₄), and evaporated to give 0.26 g. of unpurified3-(4-nitro-1,2,3-triazol-2-yl)cyclopentanecarboxylic acid.

A mixture of 3-(4-nitro-1,2,3-triazol-2-yl)cyclopentanecarboxylic acid(0.3 g.) and thionyl chloride (2 ml.) was heated at 60° for 30 minutes.The mixture was evaporated under reduced pressure and then twice treatedwith toluene (10 ml.) and re-evaporated. The non-volatile residue wastreated with ethanolic ammonia (6 M; 10 ml.). The mixture was evaporatedto give 0.25 g. of unpurified3-(4-nitro-1,2,3-triazol-2-yl)cyclopentanecarboxamide. A sample purifiedby medium pressure liquid chromatography on silica gel using EtOAc aseluant had m.p. 127°-128°.

A mixture of 3-(4-nitro-1,2,3-triazol-2-yl)cyclopentanecarboxamide (0.28g.), 5% w/w palladium on charcoal (0.3 g.) and EtOH (20 ml.) was treatedat 50° with hydrazine hydrate (0.6 ml.). The reaction was kept at 50°for 15 minutes, filtered, and evaporated to give 0.22 g. of unpurified3-(4-amino-1,2,3-triazol-2-yl)cyclopentanecarboxamide as a white solid.

A mixture of 3-(4-amino-1,2,3-triazol-2-yl)cyclopentanecarboxamide(0.215 g.), 2,2,2-trifluoroethylisothiocyanate (0.5 g.), acetonitrile (5ml.), and DMF (1 ml.) was stirred at room temperature for 3 hours. Themixture was evaporated, triturated with EtOH and filtered to give 0.35g. of solid3-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]cyclopentanecarboxamidewhich was used without further purification.

EXAMPLE 26

A mixture of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoic acid(0.2 g.), thionyl chloride (2 ml.) and THF (10 ml.) was warmed for 10minutes on a steam bath. The mixture was evaporated under reducedpressure, the residue redissolved in THF (10 ml.) and re-evaporatedunder reduced pressure. This re-evaporation procedure was repeated oncemore. The residue was dissolved in THF (10 ml.) and poured into aqueousammonia (s.g. 0.880; 20 ml.) to give a gummy precipitate. Theprecipitate was extracted into EtOAc. The extract was dried (MgSO₄),concentrated to a small volume and treated with a solution of maleicacid (0.071 g.) in a small volume of acetone to give a precipitate of0.146 g. of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzamide,m.p. 199°-201°.

The starting material may be prepared as follows:

Nitromethane (61 g.) was added to a warm (45°14 50°) solution of NaOH(61 g.) in water (122 ml.) at such a rate that the temperature wasmaintained. At the end of the addition the temperature was raised to 55°for 10 minutes and then allowed to fall back to 50°. The mixture waschilled and neutralised to pH 7 with concentrated hydrochloric acid at≧10°. The precipitated product was redissolved by the addition ofaqueous NaOH (12.5 N; 40 ml.) to give a solution of the sodium salt ofmethazonic acid.

A solution of NaNO₂ (36.2 g.) in water (300 ml.) was added duringapproximately 30 minutes to a suspension of 3-aminobenzoic acid (68.6g.) in concentrated hydrochloric acid (126.3 ml.) and water (200 ml.) at0°-5°. The mixture was filtered to give a solution of3-carboxybenzenediazonium chloride.

The solution of the sodium salt of methazonic acid was treated at 10°with a cold (5°) solution of 3-carboxybenzenediazonium chloride. Aprecipitate formed immediately and was dissolved in aqueous NaOH (33%w/w; 100 ml.) to give a dark red solution. The dark red solution wasstirred and treated at 25° with acetic anhydride (100 ml.). During thistreatment, aqueous NaOH (33% w/w, 200 ml.) was added to keep the mixturebasic. The reaction mixture was acidifed with concentrated hydrochloricacid and the precipitated product was isolated by filtration to give101.2 g. of a light brown solid. A mixture of 23.5 g. of this solid,MeOH (150 ml.) and concentrated sulphuric acid (0.5 ml.) was heatedunder reflux for 3 hours. The reaction mixture was neutralised withaqueous NaOH (1 N), concentrated, and partitioned between CHCl₃ andbrine. The CHCl₃ phase was dried (MgSO₄) and evaporated to give 5.9 g.of a red oil that crystallised slowly. The solid was purified by mediumpressure liquid chromatography on a silica gel column using EtOAc aseluant to give 5.3 g. of a solid which was recrystallised twice fromisopropanol to give 2.7 g. of methyl3-(4-nitro-1,2,3-triazol-2-yl)benzoate, m.p. 104°-106°.

A mixture of methyl 3-(4-nitro-1,2,3-triazol-2-yl)benzoate (1.0 g.), 5%w/w palladium on charcoal (0.5 g.) and HOAc (100 ml.) was stirred underone atmosphere of hydrogen until 300 ml. of hydrogen had been absorbed.The reaction was filtered and evaporated to give 0.91 g. of methyl3-(4-amino-1,2,3-triazol-2-yl)benzoate, m.p. 132°-134° afterrecrystallisation from MeOH.

A warm mixture of methyl 3-(4-amino-1,2,3-triazol-2-yl)benzoate (0.44g.) and acetonitrile (5 ml.) was treated with2,2,2-trifluoroethylisothiocyanate (0.34 g.), allowed to cool, and keptat room temperature for 21 hours. The reaction mixture was filtered,washed with ether and petroleum ether (b.p. 60°-80°), and dried to give0.63 g. of methyl3-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]benzoate,m.p. 187°-188°.

A mixture of methyl3-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,2,3-triazol-2-yl]benzoate(0.5 g.), mercuric oxide (0.4 g.) and ammoniacal EtOH (6 M; 10 ml.) wasstirred at room temperature for 2 hours. The mixture was treated withmercuric oxide (0.1 g.) and stirred for another 2 hours. The mixture wasfiltered and evaporated to give 0.47 g. of methyl3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate,m.p. 171°-173° after recrystallisation from EtOAc and petroleum ether(b.p. 60°-80°).

A mixture of methyl3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate(0.55 g.), EtOH (10 ml.) and aqueous NaOH (1 N; 1.7 ml.) was stirred atroom temperature for 18 hours. The mixture was treated with aqueous NaOH(1 N; 0.6 ml.) and kept at room temperature overnight. The mixture wasdiluted with aqueous NaOH (1 N), washed with EtOAc, acidified to pH 4,and extracted with EtOAc and THF (2:1 v/v). The extract was dried(MgSO₄) and evaporated to give 0.27 g. of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoic acidwhich was used without further purification.

EXAMPLE 27

A mixture of methyl3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate(0.12 g.), EtOH (3 ml.) and hydrazine hydrate (1 ml.) was kept at roomtemperature overnight. The reaction mixture was thrice both diluted withEtOH then evaporated to dryness. The residue was recrystallised fromMeOH to give 0.03 g. of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoic acidhydrazide, m.p. 209°-210°.

EXAMPLE 28

A mixture of methyl3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate(0.2 g.) and ethanolamine (5 ml.) was heated at 80° overnight. Themixure was evaporated and the thick oily residue was purified bychromatography on silica gel using EtOAc and isopropanol (6:1 v/v) aseluant. The product was recrystallised from isopropanol to giveN-(2-hydroxyethyl)-3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzamide,m.p. 171°-173°.

EXAMPLE 29

To a suspension of4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyric acid(0.25 g.) in THF (10 ml) at 0° was added triethylamine (0.082 g.),followed by ethyl chloroformate (0.088 g.) and the mixture was stirredfor 30 minutes. A solution of ammonia in THF (5 ml.) was added and themixture stirred again for 30 minutes, the temperature being allowed torise to room temperature. The mixture was evaporated in vacuo, aqueoussolution bicarbonate (5 ml.) was added and the mixture extracted withEtOAc (2×25 ml.) After drying (MgSO₄) the solution was filtered andevaporated in vacuo to give a pale yellow solid. This was purified bymedium pressure liquid chromatography on silica eluted with MeOH/CH₂ Cl₂(1:10 v/v) to give a solid. This was dissolved in EtOAc containing atrace of EtOH and excess of a solution of maleic acid in EtOAc wasadded. The resulting precipitate was collected by filtration andrecrystallised from EtOH to give 4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyramidemaleate, m.p. 171°-172° (30% yield).

The starting material may be prepared as follows:

To a solution of 2-amino-6-chloropyrazine (6 g.) in acetonitrile (50ml.) was added 2,2,2-trifluoroethylisothiocyanate (6 ml.) and themixture heated under reflux on a steam bath for 6 hours. The mixture wasallowed to cool, the resulting solid filtered and recrystallised fromtoluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine.

To a solution of 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine(0.7 g.) in alcoholic ammonia (35 ml.) was added yellow mercuric oxide(0.65 g.) and the mixture was stirred at room temperature overnight. Themixture was filtered and the filtrate evaporated in vacuo to give a paleyellow solid. Recrystallisation from toluene/petroleum ether (b.p.60°-80°) gave 2-chloro-6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazine,m.p. 139°-140°.

To a solution of sodium hydride (50% w/w dispersion in oil; 1.15 g.) wasadded 4-mercaptobutyric acid (1.44 g.).2-Chloro-6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazine (1.0 g.) wasadded and the mixture heated under reflux on a steam bath overnight.Water was added and the mixture washed with ether. The aqueous phase wasacidified to pH 4 with hydrochloric acid to precipitate4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyric acid asa colourless solid, which was collected by filtration, washed with waterand sucked dry. This material was used without further purification.

EXAMPLE 30

By a similar process to that described in Example 29, using anilineinstead of ammonia, there was obtainedN-phenyl-4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyramide,m.p. 165°-167° (yield 28%).

EXAMPLE 31

Thionyl chloride (1 ml.) was added dropwise to5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeric acid (0.3g.) and the mixture heated gently on a steam bath for 5 minutes. Excessthionyl chloride was removed by evaporation in vacuo and the resultinggum was covered with CH₂ Cl₂ (5 ml.). A solution of aniline (0.105 g.)in CH₂ Cl₂ (0.5 ml.) was added, followed by dropwise addition oftriethylamine until basic. After stirring at room temperature for 30minutes, the mixture was poured into water, the organic phase separatedand dried (MgSO₄). Filtration and evaporation gave an oil which wasdissolved in a small volume of EtOH and excess of a solution of maleicacid in EtOAc added. The resulting precipitate was filtered, washed withEtOH and recrystallized from EtOH to giveN-phenyl-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyramid-2-yl]valeramidemaleate. 0.25 H₂ O, m.p. 169°-171° (yield 21%).

The starting material may be prepared as follows:

Ethyl 5-cyanovalerimidate (75 g.) was stirred for 18 hours in MeOH (200ml.) containing ammonium chloride (26.4 g.). The mixture was filteredand the filtrate evaporated to dryness. The residue was then heatedunder reflux in EtOH (250 ml.) containing triethylamine (285 ml.) and2-chloroacrylonitrile (106 g.). After 2 hours the mixture was cooled,added to water (1 l.) and the pH adjusted to 4 with HOAc. The aqueousmixture was treated with charcoal, filtered and the filtrate extractedwith EtOAc (300 ml.). The aqueous layer was separated and the pHadjusted to 9 with aqueous sodium hydroxide. The aqueous mixture wasextracted with EtOAc (2×500 ml.). The combined extracts were evaporatedto dryness and the residue was recrystallised from acetonitrile to give16 g. of 5-(4-aminopyrimid-2-yl)valeronitrile.

A mixture of 5-(4-aminopyrimid-2-yl)valeronitrile (30 g.) and2,2,2-trifluoroethylisothiocyanate (30 g.) in acetonitrile (50 ml.) washeated under reflux for 18 hours. The mixture was evaporated to drynessand the residue dissolved saturated methanolic ammonia. The resultingsolution was stirred and mercuric oxide (48 g.) added. After 2 hours themixture was filtered through diatomaceous earth and the filtrateevaporated to dryness. The residue was triturated with ether and thesolid product filtered off to give 39 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrile.

To 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrile (2g.) was added concentrated HCl (10 ml.), and the mixture was heated on asteam bath for 1.75 hours. After cooling and evaporation in vacuo, theresidue was dissolved in water and brought to pH 5 with aqueous sodiumcarbonate solution. The resulting precipitate was filtered, washed withwater, then EtOH and dried at 70° under vacuum to give 1.9 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeric acid whichwas used without further purification.

EXAMPLES 32-36

The process of Example 31 was repeated, using the appropriate startingmaterials, to give the following compounds.

    ______________________________________                                         ##STR17##                                                                    Example       R                                                               ______________________________________                                        32                                                                                           ##STR18##                                                      33                                                                                           ##STR19##                                                      34                                                                                           ##STR20##                                                      35                                                                                           ##STR21##                                                      36                                                                                           ##STR22##                                                      ______________________________________                                    

Notes

Example 32: maleate, m.p. 165°-166° (yield 66%)

Example 33: maleate, m.p. 194°-196° (yield 25%)

Example 34: 2 maleate, m.p. 162°-163° (yield 45%)

Example 35: 2.5 maleate. 1H₂ O, m.p. 165°-168°

Example 36: maleate. 0.5H₂ O, m.p. 187°-189° (yield 10%).

EXAMPLE 37

To a suspension of5-[4-(2-[2,2,2-trifluoroethyl)guanidino)pyrimid-2-yl]valeric acid (0.25g.) in freshly distilled THF (10 ml.) was added triethylamine (0.093 g.)with ice cooling. After stirring 15 minutes, ethyl chloroformate (0.095g.) was added dropwise and stirred 30 minutes at 0°. Furthertriethylamine (0.093 g.) was added, followed by2,2,2-trifluoroethylamine hydrochloride (0.124 g.), and the mixture wasstirred at 0° for 30 minutes, then allowed to come to room temperature.After evaporation in vacuo, aqueous sodium carbonate solution was addedand the mixture extracted with EtOAc. The extract was dried (MgSO₄)filtered and evaporated in vacuo to give an oil which was dissolved in asmall volume of EtOAc and excess of a solution of maleic acid in EtOAcadded. Addition of ether, with scratching, caused a colourless solid toprecipitate. This was collected and recrystallised from EtOAc to giveN-(2,2,2-trifluoroethyl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrilemaleate. 0.25H₂ O, m.p. 135°-140°.

EXAMPLE 38

By a similar procedure to that described in Example 37, using3-aminopyridazine in place of 2,2,2-trifluoroethylamine, there wasobtainedN-(pyridazin-3-yl)-5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeramidemaleate, m.p. 160°-163° (yield 17%).

EXAMPLE 39

A mixture of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeronitrilehydrogen maleate, prepared as described in Example 31, (0.45 g.) andconcentrated sulphuric acid (4 ml.) was stirred at room temperature for4 hours. The mixture was then added to ice (15 g.) and the pH adjustedto 9 with aqueous sodium hydroxide. The mixture was then evaporated todryness and the solid residue extracted with a mixture of MeOH andchloroform (1:20 v/v, 150 ml.). The extract was filtered and evaporatedto dryness. The residue was treated with maleic acid in acetone to give0.15 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]valeramide hydrogenmaleate. 0.5H₂ O, m.p. 182°-185°.

EXAMPLE 40

By a similar procedure to that described in Example 39, using theappropriate starting material, there was obtained6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hexanoamide, m.p.179°-181° (yield 32%).

The starting material may be prepared by repeating the second and thirdparts of Example 31, using ethyl 6-cyanohexanimidate in place of ethyl5-cyanovalerimidate.

EXAMPLE 41

A solution of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]propanethiolhydrogen maleate (147 mg.) and sodium methoxide (70 mg.) in MeOH wastreated with 2-iodoacetamide (123 mg.) and the solution stirred at roomtemperature for 24 hours and then evaporated to dryness. The residue waspartitioned between water and EtOAc, and the EtOAc phase was dried andevaporated to dryness. The residue was purified by preparative tlc onsilica gel using EtOAc/MeOH/concentrated aqueous ammonia (s.g. 0.880)6:1:0.5 v/v/v as developing solvent to give2-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylthio]acetamideas a gum (50 mg.) which was crystallised as the hydrogen maleate salt(m.p. 168°-170°) from EtOAc.

The starting material may be obtained as follows:

A mixture of sodium methoxide (81 mg.), MeOH (10 ml.) 1,3-propanedithiol(1 ml.) and4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methanesulphinylpyrimidine (280mg.) (European patent publication No. 30092) was stirred at roomtemperature for 2 hours and then evaporated to dryness. The residue waspartitioned between aqueous 2 N HCl and ether, and the aqueous phase wasbasified with aqueous 10 N NaOH and extracted with EtOAc. The EtOAcextract was dried and evaporated to dryness and the residue crystallisedas the hydrogen maleate from acetone to give3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio)propanethiolhydrogen maleate (260 mg.), m.p. 153°-155°.

EXAMPLE 42

A mixture of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeronitrile(0.5 g.) and concentrated sulphuric acid (3 ml.) was warmed untilsolution was obtained, then stirred 2 hours at room temperature. Themixture was poured into water and basified with potassium carbonate.Extraction with EtOAc gave a yellow gum which was converted in acetoneto the maleate of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeramide (0.38g.), m.p. 192°-193° (54%).

The starting material may be prepared as follows:

4-Cyanobutanol (10 g.) was added to sodium hydride (2.75 g.) int-butanol (95 ml.) and the solution warmed to 40°.4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (11.24g.) was added over 10 minutes and the solution kept at 40° for 2 hoursthen at room temperature for 18 hours. The solvent was removed undervacuum and the residue washed with water, then ether to give5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeronitrile(8.5 g.), m.p. 134°-136°.

EXAMPLES 43-45

The process of Example 42 was repeated, using the appropriate startingmaterials, to give the following compounds.

    ______________________________________                                         ##STR23##                                                                    Example           R                                                           ______________________________________                                        43                CClF.sub.2 CH.sub.2                                         44                CHF.sub.2 CF.sub.2 CH.sub.2                                 45                CF.sub.3 CH.sub.2                                           ______________________________________                                    

Notes

Example 43: m.p. 149°-153°

Example 44: m.p. 161°-162° (yield 38%)

Example 45: m.p. 189°-191° (yield 69%).

The starting materials for the above process may be prepared byrepeating the second part of Example 42 using 3-cyanopropanol in placeof 4-cyanobutanol and using, where appropriate,2-methylsulphinyl-4-[2-(2-chloro-2,2-difluoroethyl)guanidino]pyrimidineor2-methylsulphinyl-4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]pyrimidinein place of2-methylsulphinyl-4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidine. Thesetwo pyrimidine derivatives may be prepared by repeating the second,third and fourth parts of Example 34 in European patent publication No.30092 using 2-chloro-2,2-difluoroethylisothiocyanate or2,2,3,3-tetrafluoropropylisothiocyanate respectively in place of2,2,2-trifluoroethylisothiocyanate.

EXAMPLE 46

A solution of3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrile(850 mg.) in concentrated sulphuric acid (4 ml.) was kept at 20° for 16hours then added dropwise to saturated aqueous sodium carbonate. Themixture was extracted with EtOAc (3×20 ml.) and the extract dried(MgSO₄) and evaporated in vacuo to give3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionamideas an oil. The maleic acid salt was prepared in acetone (yield 720 mg;60%), m.p. 168°-169° (decomp.).

The starting material may be prepared as follows:

2-Chloroacrylonitrile (35 ml.) was added in portions over 15 minutes toa solution of chloroacetamidine hydrochloride (55 g.) and triethylamine(120 ml.) in EtOH (250 ml.) cooled to 10°. The temperature was allowedto rise to 40° over 1 hour. The mixture was cooled and filtered and theresulting solution evaporated in vacuo. The residue was taken up inEtOAc (600 ml.) from which a tar precipitated. The solution was treatedwith decolourising carbon, filtered and evaporated to give4-amino-2-chloromethylpyrimidine as a brown solid.

The above pyrimidine (1.4 g.) and thiourea (0.8 g.) in EtOH (40 ml.)were heated under reflux for 20 minutes, a crystalline precipitate beingformed. On cooling S-[4-aminopyrimid-2-ylmethyl]isothioureahydrochloride was isolated by filtration.

The above isothiourea (2 g.) was added to a solution of potassiumhydroxide (1.1 g.) in water (20 ml.) and the solution stirred for 2hours under nitrogen. Acrylonitrile (1 ml.) was then added and themixture vigorously stirred for 30 minutes. The solution was extractedwith EtOAc, the extract dried (MgSO₄) and evaporated in vacuo to give3-[4-aminopyrimid-2-ylmethylthio]propionitrile as a gum which solidifiedon standing, m.p. 106°-9°.

To a solution of 3-(4-aminopyrimid-2-ylmethylthio)propionitrile (1.7 g.)in acetonitrile (40 ml.) was added 2,2,2-trifluoroethylisothiocyanate (2ml.) and the solution heated under reflux for 17 hours. The acetonitrilewas evaporated in vacuo and the residue dissolved in EtOAc, treated withdecolourising carbon, filtered and evaporated to give3-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylmethylthio]propionitrileas an orange solid, m.p. 108°-110°.

The above thiourea (1 g.) in DMF (10 ml.) and 8 M ammonia in EtOH (10ml.) was treated with mercuric oxide (3 g.). The mixture was stirred for40 minutes, diluted with EtOAc/water 1:1 v/v (100 ml.) and filteredthrough diatomaceous earth. The EtOAc extract was dried (MgSO₄) andevaporated in vacuo to give3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrileas an oil, which was used without further purification.

EXAMPLE 47

The process described in Example 46 was repeated, using4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]butyronitrile,to give4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]butyramide,m.p. 126°-128° (yield 45%).

The starting material may be prepared by repeating the fourth, fifth andsixth parts of Example 46 using 4-bromobutyronitrile in place ofacrylonitrile.

EXAMPLE 48

A solution oftrans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enenitrile(400 mg.) in concentrated sulphuric acid (2 ml.) was kept at 20° for 18hours then added dropwise to saturated aqueous sodium carbonate. Themixture was extracted with EtOAc (2×15 ml.) and the extract dried(MgSO₄) and evaporated in vacuo to givetrans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enamideas an oil. The maleic acid salt was prepared in acetone (yield 205 mg;36%), m.p. 177°-179°.

The starting material may be prepared as follows:

To a solution of thiophenol (50 ml.) in 2.5 M aqueous sodium hydroxide(400 ml.) stirred under nitrogen at 20° was added chloroacetamidinehydrochloride (63 g.) in water (250 ml.). The precipitated solid wascollected, pressed dry, suspended in EtOAc and the EtOAc evaporated. Thesolid was resuspended in EtOAc, a saturated solution of hydrochloricacid in EtOAc added and the mixture stirred for 30 minutes. Thehydrochloride salt of phenylthioacetamide was collected, washed withether and used directly.

Phenylthioacetamidine hydrochloride (10 g.), 2-chloroacrylonitrile (8.75g.), triethylamine (27.5 ml.) and EtOH (75 ml.) were heated under refluxtogether for 4 hours. The solution was evaporated in vacuo and theresidue partitioned between EtOAc and 1 M aqueous hydrochloric acid. Theaqueous extract was basified and extracted with EtOAc (3×100 ml.), dried(MgSO₄) and evaporated in vacuo to give a red oil containing4-amino-2-phenylthiomethylpyrimidine.

The crude 4-amino-2-phenylthiomethylpyrimidine (15 g.) in MeOH (150 ml.)and water (100 ml.) at 60° was treated over 15 minutes with sodiummetaperiodate (20 g.) in water (100 ml.). The MeOH was evaporated invacuo and the clear aqueous solution decanted from the red gum whichprecipitated. 4-Amino-2-phenylsulphinylmethylpyrimidine crystallisedfrom the aqueous solution as a white solid, m.p. 202°-204°.Recrystallisation from EtOH/ether gave an analytical sample, m.p.207°-208°.

To a solution of potassium t-butoxide (0.88 g.) in DMF (30 ml.) stirredat 0° under nitrogen was added 4-amino-2-phenylsulphinylmethylpyrimidine(1.84 g.). The solution was stirred for 10 minutes and5-bromo-valeronitrile (1.3 g.) in DMF (5 ml.) added over 5 minutes. Themixture was stirred for 30 minutes at 0°, poured into water (150 ml.)and extracted with EtOAc (4×15 ml.) and the extract dried (MgSO₄) andevaporated in vacuo to give a clear gum (1.7 g.). The gum was heated intoluene (40 ml.) at reflux for 30 minutes during which time itdissolved. The toluene was evaporated in vacuo and the residuepartitioned between CH₂ Cl₂ and 1 M aqueous hydrochloric acid. Theaqueous layer was basified with 4 M aqueous sodium hydroxide andextracted with CH₂ Cl₂ (3×15 ml.), the extract dried (MgSO₄) andevaporated in vacuo to give a clear gum (900 mg.). To this gum (900 mg.)in acetonitrile (20 ml.) was added 2,2,2-trifluoroethylisothiocyanate(500 ml.) and the solution heated under reflux for 19 hours. Theacetonitrile was evaporated in vacuo andtrans-6-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-yl]hex-5-enenitrilewas isolated from the mixture by medium pressure chromatography onsilica using EtOAc/cyclohexane 3:7 v/v as eluant.

The above thiourea (350 mg.) was dissolved in DMF (8 ml.) and 8 Mammonia in EtOH (4 ml.). Mercuric oxide (1 g.) was added and the mixturestirred for 40 minutes, then poured into water/EtOAc 1:1 (100 ml.) andthe resulting mixture filtered through diatomaceous earth. The EtOAcextract was dried (MgSO₄) and evaporated in vacuo to give trans-6-84-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enenitrile as agum which was used without further purification.

EXAMPLE 49

Methyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate(0.5 g.) in EtOH (20 ml.) was treated with 33% w/v ethanolic methylamine(7 ml.) and stirred for 18 hours at room temperature. The solution wasevaporated and the residue crystallised from aqueous EtOH to giveN-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionamide(0.35 g.), m.p. 152°-154° (73%).

The starting material may be prepared as follows:

A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazolehydrochloride (4.6 g.) in EtOH (75 ml.) and methyl 3-mercaptopropionate(2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8g. in 15 ml. of water) over 10 minutes. The resulting solution wasallowed to reach room temperature and was stirred for 1 hour. It wasthen poured into water and the precipitate filtered and crystallisedfrom EtOH to give methyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate(1.93 g), m.p. 96°-98°.

EXAMPLE 50

The process of Example 49 was repeated, using the appropriate startingmaterials, to give3-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)propionic acidhydrazide, m.p. 125°-126° (yield 69%).

EXAMPLE 51

A mixture of methyl5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate (0.4 g.)and ethanolic methylamine (33% w/v, 60 ml.) was allowed to stand at roomtemperature for 2 days. The mixture was then evaporated to dryness andthe residue recrystallised from EtOAc/ether to giveN-methyl-5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valeramide(yield 85%), m.p. 122°-126°.

The starting material may be prepared as follows:

To a solution of methyl 7-chloro-6-oxoheptanoate (2.0 g.) in hot EtOH(20 ml.) was added a solution of 2,2,2-trifluoroethylamidinothiourea(2.1 g.) in hot EtOH (20 ml.). The resulting mixture was heated underreflux for 1 hour. The mixture was then evaporated to dryness and theresidue partitioned between ether (20 ml.) and water (60 ml.). Theaqueous layer was separated and basified with sodium bicarbonate andextracted with EtOAc. The EtOAc solution was evaporated to dryness andthe residue crystallised from EtOAc/ether containing a small amount ofacetone to give methyl5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate which wasused without further purification.

EXAMPLE 52

The process of Example 51 was repeated, using the appropriate startingmaterial, to give N-methyl4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butyramide.Requires C, 47.1%, H, 6.9%, N, 26.8%. Found C, 47.0%, H, 6.7%; N, 26.8%.

The starting material may be prepared by repeating the second part ofExample 51 using methyl 6-chloro-5-oxohexanoate in place of methyl7-chloro-6-oxoheptanoate to give methyl4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butanoate.

EXAMPLE 53

A solution of methyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]cyclopentanecarboxylate(0.25 g.) in ethanolic methylamine (33% w/v, 50 ml.) was allowed tostand at room temperature for 5 days. The solution was then evaporatedto dryness and the residue in acetone treated with maleic acid to giveN-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]cyclopentanecarboxamidehydrogen maleate (yield 63%), m.p. 156°-158°.

The starting material may be prepared as follows:

A mixture of cyclopentane-1,3-dicarboxylic acid mono methyl ester (18.6g.) and thionyl chloride (50 ml.) was allowed to stand at roomtemperature for 3 hours. The mixture was then evaporated to dryness andthe residue twice evaporated to dryness from a toluene solution. Theresidue was added to an excess of diazomethane solution in ether and themixture allowed to stand at room temperature for 18 hours and thenevaporated to dryness. The residue was dissolved in acetone (100 ml.)and concentrated hydrochloric acid was added slowly until evolution ofnitrogen ceased. The resulting mixture was evaporated to low bulk andpartitioned between EtOAc and aqueous sodium bicarbonate. The EtOAclayer was separated, dried and evaporated to dryness to give methyl3-[2-chloro-1-oxoethyl]cyclopentanecarboxylate as a brown oil (16 g.).

A solution of this material (3.0 g.) in EtOH (20 ml.) was added to asolution of 2,2,2-trifluoroethylamidinothiourea (2.8 g.) in EtOH (20ml.). The mixture was heated under reflux for 2 hours and thenevaporated to dryness. The residue was partitioned between water (40ml.) and EtOAc (60 ml.). The aqueous layer was basified with sodiumbicarbonate and the precipitate extracted into EtOAc. This wasevaporated to dryness and the residue obtained purified by preparativethin layer chromatography using CHCl₃ /MeOH/aqueous ammonia (s.g. 0.880)90:10:0.1 v/v/v as eluant. The appropriate band was isolated to givemethyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]cyclopentanecarboxylate(0.64 g.) as a gum which was used without further purification.

EXAMPLE 54

A solution of crude methyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzoatehydrochloride (1 g.) in ethanolic methylamine (33% w/v, 20 ml.) wasallowed to stand at room temperature for 4 days. The mixture was thenevaporated to dryness and the residue triturated with water to give 0.16g. ofN-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzamide(yield 20%). The n.m.r. spectrum in d₆ DMSO included the followingresonances: 2.8 (d, 3H); 4.1 (m, 2H); 7.3 (s, 1H); 7.0-8.4 (complex,7H).

The starting material may be prepared as follows:

A solution of 3-cyanophenacyl chloride (3.6 g.) in warm EtOH (30 ml.)was added to a solution of 2,2,2-trifluoroethylamidinothiourea (4.0 g.)in EtOH (30 ml.). The mixture was then heated under reflux for 1 hourand evaporated to low volume. On cooling this solution deposited3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzonitrilehydrochloride (4.4 g.). The n.m.r. in d₆ DMSO included the followingresonances: 4.4 (m, 2H); 7.5-9.2 (complex, 8H).

The above material (4.3 g.) was heated under reflux in a mixture of HOAC(30 ml.) and concentrated aqueous HCl (30 ml.) for 2 hours. The solutionwas then evaporated to dryness and the residue dissolved in MeOH (100ml.). To this was added thionyl chloride (20 ml.) dropwise. The solutionwas then evaporated to dryness to give crude methyl3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzoatehydrochloride which was used without further purification.

EXAMPLE 55

A solution of5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile(0.15 g.) in concentrated sulphuric acid (3 ml.) was stirred for 1.5hours at room temperature then poured onto ice and basified withconcentrated aqueous ammonia. Extraction with EtOAc gave 0.12 g. of awhite solid which was triturated with ether to give5-[3-(2-]2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramide(0.085 g., 54%), m.p. 162°-164°.

The starting material may be prepared as follows:

3-Amino-1,2,4-triazole (4.2 g.) was added to a solution of sodiummethoxide in MeOH (1.2 g. sodium in 30 ml. MeOH) and the solutionstirred for 0.5 hours at room temperature. 5-Bromovaleronitrile (8.1 g.)was added and the solution heated under reflux for 12 hours. Thesolution was evaporated and the residue partitioned between water andEtOAc. The extracts were washed with brine, dried over MgSO₄ andevaporated to give a pale yellow oil (6.5 g.) which was purified bymedium pressure liquid chromatography using EtOAc/MeOH 6:1 v/v aseluant. The colourless oil obtained was used without characterisationfor the following reaction. The crude1-(4-cyanobutyl)-3-amino-1,2,4-triazole (5.45 g.) in acetonitrile (80ml.) was treated with 2,2,2-trifluoroethylisothiocyanate (4.4 g.) andthe solution heated under reflux for 3.5 hours. Evaporation gave a whitesticky solid which was triturated with ether/EtOH to give5-(3-[3-(2,2,2-trifluoroethyl)thioureido]-1,2,4-triazol-1-yl)valeronitrile(4.04 g.) as a white solid, m.p. 136°-138°.

This nitrile (3.6 g.) in MeOH (80 ml.) and acetonitrile (5 ml.) wastreated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.).After stirring for 1.5 hours the black suspension was filtered throughdiatomaceous earth and the filtrates evaporated to give a white solid.The solid was washed with ether and filtered to give5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile(2.87 g.) as a white solid, m.p. 200°-201° after recrystallisation fromEtOH.

EXAMPLE 56

A solution of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,3,5-triazin-2-ylthio]valeronitrile(0.25 g.) in concentrated sulphuric acid (1 ml.) was kept at roomtemperature for 4 hours. The reaction mixture was diluted with an equalvolume of ice, basified with aqueous NaOH and then filtered to give awhite solid. This solid was dissolved in a small volume of EtOH andacetone and treated with a solution of maleic acid (0.09 g.) in a smallvolume of acetone. The mixture was left at room temperature overnightand then filtered to give 0.15 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,3,5-triazin-2-ylthio]valeramidemaleate, m.p. 166°-168° after recrystallisation from EtOH.

The starting material may be prepared as follows:

A stirred mixture of 2-mercapto-4-amino-1,3,5-triazine (5.1 g.), 10% w/vaqueous NaOH (16 ml.) and 5-bromovaleronitrile was kept at roomtemperature for 3 hours. The mixture was filtered to separate a firstcrop of product. The filtrate was kept at room temperature overnight andrefiltered to yield another crop of product. These crops were washedwith ether and recrystallised from EtOH to give 6.7 g. of5-(4-amino-1,3,5-triazin-2-ylthio)valeronitrile, m.p. 123°-125°.

A stirred mixture of 5-(4-amino-1,3,5-triazin-2-ylthio)valeronitrile(0.9 g.) and THF (30 ml.) was kept under argon at -60° and treated witha solution of n-butyllithium in hexane (1.6 M; 3.1 ml.). The mixture wasstirred at -60° for 30 minutes and then treated with2,2,2-trifluoroethylisothiocyanate (0.7 g.). The mixture was allowed towarm to room temperature and stirred overnight. The mixture was pouredinto water and acidified with a small volume of concentratedhydrochloric acid. The aqueous and organic phases were separated. Theaqueous phase was extracted with EtOAc and the extract was combined withthe organic phase from the reaction mixture. The combination was dried(MgSO₄) and evaporated to give a sticky solid that was triturated withpetroleum ether (b.p. 40°-60°) and EtOAc and filtered to give 1.0 g. of5-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,3,5-triazin-2-ylthio]valeronitrile,m.p. 136°-137° after recrystallisation from EtOH.

A stirred suspension of5-[4-(3-[2,2,2-trifluoroethyl]thioureido)-1,3,5-triazin-2-ylthio]valeronitrile(2.0 g.) in ammoniacal EtOH (6 M; 40 ml.) was treated at roomtemperature with mercuric oxide (2.0 g.). After about 1 hour the mixturewas diluted with DMF (20 ml.). The mixture was kept at room temperatureovernight, filtered, and evaporated. The non-volatile residue wasdissolved in DMF (40 ml.) and ammoniacal EtOH (6 M; 20 ml.) and treatedat room temperature with mercuric oxide (1 g.). The mixture was stirredfor 4 hours and then filtered. The filtrate was evaporated to dryness,redissolved in EtOH and saturated with H₂ S gas. The mixture wasfiltered, evaporated to dryness, redissolved in EtOAc (15 ml.),refiltered, treated with a solution of maleic acid (0.66 g.) in a smallvolume of acetone, and then diluted with petroleum ether (b.p. 60°-80°)to give a solution from which the product gradually precipitated. Theprecipitate was filtered, washed with a small volume of cold acetone andthen with petroleum ether (b.p. 60°-80°) to give 1.6 g. of5-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,3,5-triazin-2-ylthio]valeronitrilemaleate, m.p. 155°-156° after recrystallisation from EtOH.

EXAMPLE 57

To a solution of4-(2-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]ethoxymethyl)benzonitrile(650 mg.) in MeOH (5 ml.) was added hydrogen peroxide (30%, 100 volume)(2 ml.) followed by N aqueous NaOH (1 ml.). The mixture was then stirredat room temperature for 2.25 hours. The solvent was then evaporated invacuo to give a yellow gum (700 mg.). This gum was purified by mediumpressure chromatography using EtOAc/EtOH/triethylamine 96:3:1 v/v/v aseluant to give4-(2-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]ethoxymethyl)benzamide(210 mg.; 31%) having the following n.m.r. in d₆ DMSO: 7.5 (m, 4H); 7.5(d, 1H); 5.8 (d, 1H); 5.0 (s, 2H); 4.0 (m, 4H); 3.7 (m, 2H).

The starting material may be prepared as follows:

2-Hydroxyethylhydrazine (7.6 g.) was added slowly to a solution ofpotassium carbonate (13.8 g.) in water (40 ml.). The mixture was cooledto 0°, then 2-chloroacrylonitrile (8.75 g.) was added slowly withvigorous stirring. Stirring was continued for a further 17 hours and themixture was then continuously extracted with EtOAc for 20 hours. Onevaporation of the solvent, 3-amino-1-(2-hydroxyethyl)pyrazole wasobtained, (7.7 g.; 60%), b.p. 170°/0.5 mm.

A solution of 2,2,2-trifluoroethylisothiocyanate (13.8 g.) and3-amino-1-(2-hydroxyethyl)pyrazole (12.5 g.) in acetonitrile dried over4A molecular sieve (30 ml.) was stirred at room temperature for 4 hours.A precipitate formed after 30 minutes. Filtration gave1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (12.1g.; 46%), m.p. 145°-146°.

To a solution of1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (20.0g.) in 5 N ammonia in EtOH solution (700 ml.) was added yellow mercuricoxide (64.8 g.) with stirring. Stirring was continued for a period of 2hours. The mixture was filtered through diatomaceous earth and thesolvent then evaporated to dryness in vacuo. The residual oil wastriturated with ether to give1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (18.5g.; 99%), m.p. 82°.

A mixture of1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (2.51g.) and p-cyanobenzyl bromide (1.96 g.) was heated at 140° for 10minutes. The melt, on cooling, was dissolved in MeOH (5 ml.) andpurified by chromatography on silica gel using EtOAc/EtOH/triethylamine9:1:1 v/v/v as eluant to give4-(2-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]ethoxymethyl)benzonitrile(700 mg.; 19%).

EXAMPLE 58

To a solution of4-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-ylmethyl)benzamide(180 mg.) in EtOH saturated with ammonia (5 ml.) was added yellowmercuric oxide (380 mg.). The mixture was stirred at room temperaturefor 17 hours. The mixture was centrifuged, then the supernatant liquorwas evaporated in vacuo to give4-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-ylmethyl]benzamide,m.p. 192° (from EtOH/petroleum ether (b.p. 60°-80°)).

The starting material may be prepared as follows:

Sodium hydride paste (61% w/w dispersion in oil, 70 mg.) was added to asolution of 3-nitropyrazole (200 mg.) in dry DMF (2.5 ml.) withstirring. When effervescence had ceased, 4-chloromethylbenzamide (300mg.) was added. The mixture was stirred at room temperature for 2 days,then diluted with water (20 ml.). The precipitated4-[3-nitropyrazol-1-ylmethyl]benzamide (300 mg.), m.p. 200°-201°, wascollected by filtration.

A solution of the above nitro amide (100 mg.) in dry DMF washydrogenated at room temperature and at atmospheric pressure using 5%w/w palladium on carbon (10 mg.) as catalyst. Filtration and subsequentevaporation in vacuo of the filtrate gave4-[3-aminopyrazol-1-ylmethyl]benzamide.

A mixture of the above amine (250 mg.) and2,2,2-trifluoroethylisothiocyanate (0.16 g.) in acetonitrile (1 ml.) wasstirred at room temperature for 3 hours. The precipitated solid wasfiltered off to give4-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-ylmethyl)benzamide(180 mg.), m.p. 205°-206°.

EXAMPLE 59

A solution of4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyric acid (84mg.) and triethylamine (0.2 ml.) in DMF (5 ml.) was stirred at 0° whileisobutylchloroformate (68 mg.) was added. The solution was kept at 0°for 0.5 hours, treated with a saturated solution of ammonia in EtOH (1ml.) and then stirred at room temperature for 18 hours. The solution wasevaporated to dryness and the residue partitioned between N aqueous HCland EtOAc. The aqueous phase was basified with 10 N aqueous NaOH andextracted with EtOAc, and the extract was dried and evaporated todryness to give4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyramide (60mg.) which was crystallised as the hydrogen maleate salt from acetone,m.p. 138°-141°.

The starting material may be prepared as follows:

A mixture of 4-mercaptobutyric acid (0.72 g.) a 50% w/w dispersion ofsodium hydride in mineral oil (0.58 g.) and 2-ethoxyethanol (5 ml.) wastreated with 2-amino-6-bromopyridine (0.35 g.) and the mixture washeated under reflux for 18 hours and then evaporated to dryness. Theresidue was partitioned between water and EtOAc and the aqueous phasewas neutralised with HOAc. The precipitated yellow solid was collectedto give 4-(6-aminopyrid-2-ylthio)butyric acid (0.27 g.) which was usedwithout further purification.

A mixture of 4-(6-aminopyrid-2-ylthio)butyric acid (0.21 g.), DMF (3ml.) and 2,2,2-trifluoroethylisothiocyanate (0.15 g.) was left at roomtemperature for 18 hours and then evaporated to dryness. A solution ofthe residue in methanolic ammonia was treated with yellow mercuric oxide(0.43 g.) and the mixture stirred at room temperature for 1 hour. Themixture was filtered and the filtrate evaporated to dryness and theresidue treated with 2 N aqueous NaOH (5 ml.) and then filtered. Thefiltrate was acidified with HOAc and the precipitate collected to give4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyric acid(0.17 g.) which was used without further purification.

EXAMPLE 60

The process of Example 59 was repeated, using the appropriate startingmaterial, to give5-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]valeramidemaleate, m.p. 138°-139° (yield 69%).

The starting material may be prepared by repeating the second and thirdparts of Example 59 using 5-mercaptovaleric acid in place of4-mercaptobutyric acid to give5-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]valeric acid.

EXAMPLE 61

A solution of4-[6-(2[2,2,2-trifluoroethyl]guanidino)pyrid-2-yloxy]butyronitrile (0.2g.) in concentrated sulphuric acid was kept at room temperature for 6hours and then diluted with water and basified with 10 N aqueous NaOH.The solution was extracted three times with EtOAc, and the combinedextracts dried and evaporated to dryness. A solution of the residue inacetone was added to a solution of maleic acid in acetone, and thecrystalline precipitate was collected to give4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-yloxy]butyramidehydrogen maleate (0.14 g.), m.p. 176°-177°.

The nitrile used as starting material may be prepared as follows:

A mixture of 4-hydroxybutyronitrile (0.85 g.), a 50% w/w dispersion ofsodium hydride in mineral oil (0.48 g.) and sulpholane (5 ml.) wasstirred at room temperature for 1 hour. The mixture was treated with2-amino-6-bromopyridine (0.87 g.) and the mixture heated with stirringat 130° for 18 hours. The cooled mixture was diluted with water (20ml.), acidified with concentrated aqueous HCl and washed with ether. Theaqueous phase was basified with 10 N aqueous NaOH, extracted three timeswith EtOAc and the combined extracts dried and evaporated to dryness.

A solution of the residue in acetonitrile (5 ml.) was treated with2,2,2-trifluoroethylisothiocyanate, and the solution heated under refluxfor 1 hour and then evaporated to dryness. The residue was stirred with2 N aqueous HCl (20 ml.) and ether (20 ml.) and the insoluble materialcollected.

The solid was dissolved in methanolic ammonia solution, and the solutiontreated with yellow mercuric oxide (2 g.) and then stirred at roomtemperature for 18 hours. The mixture was filtered and the filtrateevaporated to dryness to give4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-yloxy]butyronitrile (1.0g.) which was used without further purification.

EXAMPLE 62

In a similar manner to the process described in Example 61, using4-[2-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrid-6-ylthio]butyronitrileas starting material, there was obtained4-[2-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrid-6-ylthio]butyramidemaleate, m.p. 173°-174° (yield 58%).

The above nitrile may be prepared in an analogous manner to the butyricacid described in Example 59, using 4-mercaptobutyronitrile in place of4-mercaptobutyric acid and 2,2,3,3-tetrafluoropropylisothiocyanate inplace of 2,2,2-trifluoroethylisothiocyanate.

EXAMPLE 63

A mixture of 5-(3-aminopyrazol-1-yl]valeramide (18.2 mg.) and(2,2,2-trifluoroethyl)-S-methylisothiourea hydroiodide (51 mg.) washeated at 100° for 20 minutes. Preparative high pressure liquidchromatography on silica gel, using CHCl₃ /MeOH/ammonia (s.g. 0.880)8:2:0.5 v/v/v as eluant gave5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p.129°-130° (40%).

The isothiourea used as starting material may be prepared as follows:

A solution of ammonium thiocyanate (9.12 g.), and2,2,2-trifluoroethylamine hydrochloride (13.6 g.) in water (50 ml.) washeated at 100° for 20 hours. Water (50 ml.) was added and the mixturereheated to redissolve the solid. On cooling crystals of2,2,2-trifluoroethylthiourea hydrate, m.p. 154°-156° (52.4%), wereprecipitated.

A solution of 2,2,2-trifluoroethylthiourea (8.0 g.) and methyl iodide(3.5 g.) in EtOH (40 ml.) was heated under reflux for 70 minutes, thenevaporated to dryness in vacuo. The residue was triturated with ether togive 2,2,2-trifluoroethyl-S-methylisothiourea hydroiodide, m.p.154°-156° (90%).

EXAMPLE 64

A tablet containing 50 mg. of5-[3-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrazol-1-yl]valeramide maybe prepared using ingredients in the following proportions:

    ______________________________________                                                             mg./tablet                                               ______________________________________                                        (a)    Tablet Core.                                                                  Active agent        50                                                        Lactose             218.5                                                     Calcium carboxymethylcellulose                                                                    22.5                                                      Polyvinylpyrrolidone                                                                              6.0                                                       Magnesium stearate  3.0                                                (b)    Tablet Coat                                                                   Hydroxypropylmethylcellulose                                                                      4.5                                                       Polyethylene glycol 0.9                                                       Titanium dioxide    1.35                                               ______________________________________                                    

The active agent, lactose and calcium carboxymethylcellulose are mixed.An aqueous solution of polyvinylpyrrolidone is added, and the mass isthen mixed until it is suitable for granulation. The mass is thengranulated and dried. The magnesium stearate is blended with the driedgranules and the resulting mixture is compressed into tablets. Thetablets are film-coated using an aqueous or solvent suspension ofhydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide.

We claim:
 1. A guanidine derivative of the formula I: ##STR24## in whichR¹ and R², which may be the same or different, are hydrogen or branchedor unbranched 1-10C alkyl, 3-8C cycloalkyl or 4-14C cycloalkylalkyls,each alkyl, cycloalkyl or cycloalkylalkyl being optionally substitutedby one or more halogens selected from fluorine, chlorine and bromine,provided that at least one of R¹ and R² is a halogen-substituted alkyl,cycloalkyl or cycloalkylalkyl, and provided that there is no halogensubstituent on the carbon of the alkyl, cycloalkyl or cycloalkylalkylwhich is directly attached to the nitrogen atom;in ring X is selectedfrom oxazole, thiazole, imidazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole,1,2,3-triazole, 1,2,4-triazole and pyrazole, and which heterocyclic ringmay, where possible, carry one or two optional substituents, theoptional substituents on ring X being selected from fluorine, chlorine,bromine, 1-6C alkyl, 1-6C alkoxy, trifuloromethyl, hydroxy and aminoradicals; --A-- is a phenylene or 5-7C cycloalkylene radical or a 1-8Calkylene chain which is optionally substituted by one or two 1-3C alkylsradicals and into which is optionally inserted, as part of the backboneof the chain, one or two groups selected from oxygen and sulphur atomsand NH, 1-6C N-alkyl, cis and trans vinylene, ethynylene, phenylene and5-7C cycloalkylene radicals, provided that the shortest link betweenring X and C═D is of at least 3 atoms, provided that when an optionalinsertion is made in chain A which results in the inserted group beingdirectly attached to C═D the inserted group is other than an oxygen orsulphur atom or an NH or N-alkyl radical, and provided that no twoinsertions selected from oxygen and sulphur atoms and NH and N-alkylradicals are directly attached one to the other; D is an oxygen orsulphur atom; R³ is a hydrogen atom or a hydroxy, amino, 1-6Calkyl-amino, 1-C haloalkylamino, 1-6C alkanoylamino, 1-6C alkyl, 3-8Ccycloalkyl, 4-12C cycloalkylalkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6Chaloalkyl, 1-6C alkoxy, 1-6C hydroxyalkyl, 2-10C alkoxyalkyl, 2-10Calkylthioalkyl, 1-6C aminoalkyl, 2-8C alkylaminoalkyl, 3-12Cdialkylaminoalkyl, 2-8C alkanoylaminoalkyl, 8-14C benzoylaminoalkyl,3-10C alkoxycarbonylalkyl, 2-8C carbamoylalkyl, phenyl, 7-11Cphenylalkyl, heteroaryl or heteroarylalkyl radicals, wherein theheteroaryl part is a furan, thiophene, pyrrole, thiazole, oxazole,imidazole, thiadiazole, oxadiazole, triazole, pyrazole, pyridine orpyrimidine ring, wherein the alkyl part of the heteroarylalkyl radicalis 1-6C and wherein, when R³ is or contains a phenyl or heteroaryl ring,that ring is optionally substituted by one or two groups selected fromfluorine, chlorine, bromine and iodine atoms and 1-6C alkyl, 1-6Calkoxy, 1-6C alkylthio, 2-6C dialkylamino, 2-6C alkanoyl,trifluoromethyl, hydroxy and amino radicals; R⁴ is a hydrogen atom or R³and R⁴ are joined to form, together with the nitrogen atom to which theyare attached, a pyrrolidine, piperidine, morpholine, pipevazine orN-methylpiperazine ring; and the pharmaceutically-acceptableacid-addition salts thereof.
 2. A guanidine derivative of the formula Igiven in claim 1 in which R¹ and R² are selected from the groupconsisting of hydrogen atoms, and 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2-bromo-2,2-difluoroethyl,2,2-dibromo-2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl,2,2-difluoroethyl, 2,2-dichloroethyl, 2-chloro-2-fluoroethyl,2-bromo-2-fluoroethyl, 2,2,3,3-tetrafluoropropyl,2,2,3,3,3-pentafluoropropyl, 1,1,1,3,3,3-hexafluoroisopropyl,1,3-dichloro-1,1,3,3-tetrafluoroisopropyl,1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl,2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3-tetrafluorocyclopropyl,2-chloro-2,3,3-trifluorocyclopropyl, 2,2-difluorocyclopropyl,2-chloro-3,3-difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl,2-chloro-2,3,3,4,4-pentafluorocyclobutyl,(1,2,2,3,3-pentafluorocyclopropyl)methyl,(2-chloro-1,2,3,3-tetrafluorocyclopropyl)methyl,(1,2,2,3,3,4,4-heptafluorocyclobutyl)methyl,(2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl)methyl, methyl, ethyl,propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl andcyclopropylbutyl radicals provided that at least one of R¹ and R² is ahalogen-substituted radical; the optional substituents on ring X areselected from fluorine, chlorine, bromine, methyl, methoxy methylthio,trifluoromethyl, hydroxy and amino radicals; --A-- is a phenylene,cyclopentylene, cyclohexylene, trimethylene, tetramethylene,pentamethylene, thioethylene, thiotrimethylene, thiotetramethylene,thiopentamethylene, oxyethylene, oxytrimethylene, oxytetramethylene,methylenethiomethylene, methylenethioethylene, methylenethiopropylene,methyleneoxymethylene, methyleneoxyethylene, ethyleneoxyethylene,oxy-2-methylethylene, thiopropylenethiomethylene,oxyethyleneoxymethylene, iminopropylene, iminoethylene,vinylenepropylene, oxymethylene-vinylene, 1,3-phenylene,1,3-cyclopentylene, methylene-1,4-phenylene,ethyleneoxymethylene-1,4-phenylene, oxy-1,3-phenylenemethylene orthiomethylene-ethynylenemethylene radical;D is an oxygen or sulphuratom; R³ is a hydrogen atom or a hydroxy, amino, methylamino,2,2,2-trifluoroethylamino, acetylamino, methyl, cyclohexyl,cyclohexylmethyl, allyl, propargyl, 2,2,2-trifluoroethyl, methoxy,2-hydroxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-aminoethyl,2-methylaminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl,2-benzoylaminoethyl, methoxycarbonylmethyl, 2-carbamoylpropyl, phenyl,benzyl, heteroraryl, and heteroarylmethyl wherein the heteroaryl part isa furan, thiophene, pyrrole, thiazole, oxazole, imidazole, thiadiazole,oxadiazole, triazole, pyrazole, pyridine or pyrimidine ring and whereinwhen R³ is or contains a phenyl or heteroaryl ring that ring isoptionally substituted by one or two groups selected from fluorine,chlorine, bromine and iodine atoms and methyl, methoxy, methylthio,dimethylamino, acetyl, trifluoromethyl, hydroxy and amino radicals; R⁴is a hydrogen atom, or R³ and R⁴ are joined to form, together with thenitrogen atom to which they are attached, a pyrrolidine, piperidine,morpholne, piperazine or N-methylpiperazine ring; and thepharmaceutically-acceptable acid-addition salts thereof.
 3. A guanidinederivative as claimed in claim 2 in which R³ and R⁴ are hydrogen atoms.4. A guanidine derivative as claimed in claim 3 in which R² is ahydrogen atom and R¹ is 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethylor or 2,2,3,3-tetrafluoropropyl radical.
 5. A guanidine derivative asclaimed in claim 4 in which ring X is a pyrazole, 1,2,3-triazole,1,2,4-triazole in which A is linked at the 1-position, ring.
 6. Aguanidine derivative as claimed in claim 5 in which --A-- is atetramethylene, pentamethylene, oxytrimethylene, oxytetramethylene,thiatrimethylene or thiatetramethylene radical.
 7. A guanidinederivative selected from the group consisting of5-[3-(2-[2,2,2-trifluoroethyl]guanidino]pyrazol-1-yl]valeramide,5-[3-(2-[2,2,3,3-tetrafluoropropyl]guanidino)pyrazol-1-yl]valeramide,5-[3-(2-[2-chloro-2,2-difluoroethyl]guanidino)pyrazol-1-yl]valeramide,-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]valeramide,5-[4-(2-[2,2,3,3-tetrafluoropropyl]guanidino)-1,2,3-triazol-2-yl]valeramide,6-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]hexanomideand the pharmaceutically-acceptable acid-addition salts thereof.
 8. Apharmaceutical composition which comprises a guanidine derivative asclaimed in claim 1 in an amount effective to inhibit gastric acidsecretion in a living animal and in association with apharmaceutically-acceptable diluent or carrier.
 9. A method ofinhibiting gastric acid secretion in a living animal comprisingadministering to the animal the composition of claim 8.